ASBT inhibitors for treatment of kidney disease

Abstract

The present invention relates to apical sodium dependent bile acid transport (ASBT) inhibitors for the treatment of kidney diseases and disorders, such as biliary nephropathy. Such treatments may include lowering serum bile acid concentration, increasing urine bile acid, and improving liver and kidney parameters.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to Swedish Patent Application No. 2251441-8, filed on December 9, 2022, the disclosure of which is incorporated herein by reference in its entirety. Technical field

[0003] The present invention relates to apical sodium-dependent bile acid transporter (ASBT) inhibitors for the treatment of kidney diseases and disorders (such as cholemic nephropathy). Such treatments include reducing serum bile acid concentration, increasing urinary bile acids, and improving liver and kidney parameters. Background art

[0004] Cholemic nephropathy is a state of kidney injury / failure in patients with obstructive jaundice. Also known as biliary cast nephropathy, bile acid nephropathy, icteric nephrosis / nephropathy, or jaundice-associated nephropathy, cholemic nephropathy represents an underestimated but important cause of renal dysfunction in cholestasis or advanced liver disease with jaundice. Cholemic nephropathy is a common complication in patients with liver diseases (such as cirrhosis, alcoholic steatohepatitis, drug-induced cholestatic liver injury, and fulminant hepatitis) and is associated with high morbidity and mortality. Cholemic nephropathy is characterized by hemodynamic alterations in the liver, kidney, and systemic circulation, intratubular cast formation, and tubular epithelial cell injury, but its underlying pathophysiological mechanisms are not well understood.

[0005] Toxic bile acids have been considered to play a role in the development of cholestatic renal injury (Fickert et al., Hepatology 2013, vol. 58, p. 2056-2069; Krones et al., Dig. Dis. 2015, vol. 33, p. 367-375; Tinti et al., Life 2021, vol. 11, 1200). The less toxic bile acid norursodeoxycholic acid has been shown to improve renal injury and has been proposed as a medical treatment for cholemic nephropathy (Krones et al., J Hepatol. 2017, vol. 67, p. 110-119).

[0006] Despite the increasing interest in cholemic nephropathy and the growing understanding of the mechanisms leading to this disease, there is currently no specific treatment available for this condition. Description of the drawings

[0007] Figure 1 shows a graph of the blood chemistry analysis of mice during 12 weeks after bile duct ligation (BDL) or sham surgery. Figure 1A : alanine aminotransferase (ALT) level;Figure 1B : Aspartate aminotransferase (AST) level; Figure 1C : Alkaline phosphatase (ALP) level; Figure 1D : Total bilirubin level.

[0008] Figure 2 shows the graphs of bile acid transporter expression during 12 weeks after BDL or sham operation. Figure 2A : Sinusoidal uptake transporter NTCP; Figure 2B : Sinusoidal uptake transporter Cyp7a1; Figure 2C : Apical transporter Bsep; Figure 2D : Sinusoidal efflux transporter MRP4.

[0009] Figure 3 shows the graphs of the expression of apical uptake transporters ASBT ( Figure 3A ) and OATP1a1 ( Figure 3B ), apical efflux transporter MRP4 ( Figure 3C ), and basolateral efflux transporters MRP3 ( Figure 3D ) and OSTα ( Figure 3E ) during 12 weeks after BDL or sham operation.

[0010] Figure 4 Shows the graph of the total concentration of bile acids in urine after treating BDL mice with different doses of Compound 1.

[0011] Figure 5 shows the graph of the concentration of each bile acid in urine after treating BDL mice with different doses of Compound 1. Figure 5A : Tauro-α / β-muricholate; Figure 5B : Taurocholate; Figure 5C : Taurocholic acid sulfate.

[0012] Figure 6 Shows the graph of the total concentration of bile acids in urine after treating mice (BDL or sham operation) with vehicle or Compound 1 for 6 weeks.

[0013] Figure 7 Is the graph of the concentration of each bile acid (ω-muricholate, tauro-ω-muricholate, tauro-α / β-muricholate, and β-muricholate) in urine after treating mice (BDL or sham operation) with vehicle or Compound 1 for 6 weeks.

[0014] Figure 8 Is the graph of the concentration of each bile acid (glycocholate, tauroursodeoxycholate, taurocholate, and cholate) in urine after treating mice (BDL or sham operation) with vehicle or Compound 1 for 6 weeks.

[0015] Figure 9 Graph showing the concentrations of individual bile acids (ursodeoxycholate, hyodeoxycholate, taurochenodeoxycholate, and taurodeoxycholic acid) in the urine of mice (BDL or sham-operated) after 6 weeks of treatment with vehicle or Compound 1.

[0016] Figure 10 Graph showing the concentrations of individual bile acids (chenodeoxycholate, deoxycholate, taurolitocholate, and taurocholic acid sulfate) in the urine of mice (BDL or sham-operated) after 6 weeks of treatment with vehicle or Compound 1.

[0017] Figure 11 Graph showing the change in body weight of mice (BDL or sham-operated) during 6 weeks of treatment with vehicle or Compound 1.

[0018] Figure 12 Graph showing the survival of mice (BDL or sham-operated) during 6 weeks of treatment with vehicle or Compound 1.

[0019] Figure 13 Graph showing the concentration of the urinary biomarker neutrophil gelatinase-associated lipocalin (NGAL) in mice (BDL or sham-operated) during 6 weeks of treatment with vehicle or Compound 1.

[0020] Figure 14 Graph showing the concentration of the urinary biomarker kidney injury molecule-1 (KIM-1) in mice (BDL or sham-operated) during 6 weeks of treatment with vehicle or Compound 1.

[0021] Figure 15 shows a graph of the blood chemistry analysis of mice (BDL or sham-operated) during 6 weeks of treatment with vehicle or Compound 1. Figure 15A : Alanine aminotransferase (ALT) level; Figure 15B : Aspartate aminotransferase (AST) level; Figure 15C : Alkaline phosphatase (ALP) level; Figure 15D : Total bilirubin level; Figure 15E : Blood urea nitrogen (BUN) level.

[0022] Figure 16 shows a graph of the expression of different bile acid transporters in mice (BDL or sham-operated) after 6 weeks of treatment with vehicle or Compound 1. Figure 16A : NTCP; Figure 16B : Bsep; Figure 16C : OATP; Figure 16D : MRP2; Figure 16E : MRP3; Figure 16F : Cyp7a1; Figure 16G : MRP4.

[0023] Figure 17 shows a graph of the expression of different bile acid transporters in mice (BDL or sham) after 6 weeks of treatment with vehicle or compound 1. Figure 17A : ASBT; Figure 17B : OATP2b1; Figure 17C : OATP1a1; Figure 17D : MRP2; Figure 17E : MRP3; Figure 17F : MRP4; Figure 17G : OST-α.

[0024] Figure 18 shows a graph of the survival rate (%) in mice (BDL or sham) after 28 days of treatment with vehicle or compound 1, with treatment starting at different times after BDL or sham. Figure 18A : Treatment starting on day 3; Figure 18B : Treatment starting on day 21; Figure 18C : Treatment starting on day 42; Figure 18D : Treatment starting on day 63.

[0025] Figure 19 shows a graph of the change in body weight (%) in mice (BDL or sham) after 28 days of treatment with vehicle or compound 1, with treatment starting at different times after BDL or sham. Figure 19A : Treatment starting on day 3; Figure 19B : Treatment starting on day 21; Figure 19C : Treatment starting on day 42; Figure 19D : Treatment starting on day 63.

[0026] Figure 20 shows a graph of the total concentration of bile acids in serum ( Figure 20A ) and urine ( Figure 20B ) in mice (BDL or sham) after 19 days of treatment with vehicle, compound 1, or compound 2.

[0027] Figure 21 Shows a graph of the concentration of the urinary biomarker NGAL in mice (BDL or sham) after 19 days of treatment with vehicle, compound 1, or compound 2. (Data are presented as mean ± SEM).

[0028] Figure 22 shows a graph of the total concentration of bile acids in serum ( Figure 22A ) and urine ( Figure 22B ) in BDL mice after 5 days of treatment with vehicle or different ASBT inhibitors. (Data are presented as mean ± SEM); p < 0.01 & p > 0.001 by one-way ANOVA, followed by Dunnett's multiple comparison test; relative to BDL control p > 0.0001 was determined by Student's Unpaired T - test).

[0029] Figure 23 Figure showing the concentration of urinary biomarker NGAL in BDL mice treated with vehicle or different ASBT inhibitors for 5 days. (Data are presented as mean ± SEM); relative to the BDL control group p < 0.05 was determined by one - way ANOVA analysis, followed by Dunnett's multiple comparison test; relative to the BDL control p > 0.05 & p < 0.01 was determined by Student's Unpaired T - test).

[0030] Figure 24 shows the concentration of ASBT inhibitor in serum at 2 hours and 6 hours after dosing on day 8. Figure 24B : Compound X; Figure 24B : Compound 5. (Data are presented as mean ± SEM).

[0031] Figure 25 Figure showing the concentration of Compound X and Compound 5 in urine on day 8. (Data are presented as mean ± SEM). DETAILED DESCRIPTION OF THE INVENTION

[0033] The apical sodium - dependent bile acid transporter (ASBT, also known as ileal bile acid transporter (IBAT), ISBT, ABAT or NTCP2; gene symbol SLC10A2) is expressed in the apical membrane of ileal enterocytes, renal proximal tubular epithelial cells, bile duct epithelial cells, large bile duct cells and gallbladder epithelial cells. In the ileum, where ASBT is mainly expressed, it mediates the reabsorption of conjugated bile acids for recycling back to the liver. Inhibition of ASBT disrupts the enterohepatic circulation and leads to fecal elimination of bile acids similar to surgical interruption of the enterohepatic circulation. Removal of bile acids from the enterohepatic circulation results in decreased bile acid levels in serum and liver. Thus, ASBT inhibitors have been developed for the treatment of liver diseases associated with elevated bile acid levels.

[0034] ASBT is also expressed in the proximal tubular epithelial cells of the kidney. Thus, systemically available ASBT inhibitors can also inhibit bile acid reuptake in the kidney. It is believed that this leads to increased bile acid levels in urine and increased removal of bile acids from the body via urine. Thus, targeting renal ASBT may be an additional means of increasing bile acid excretion, thereby further reducing the bile acid load in serum and liver.

[0035] Many agents that are not cleared by the diseased liver ultimately enter renal tissue, where they may cause kidney disease. It is not currently known through which mediators the diseased liver causes kidney injury, but candidate mediators are bile acids, bilirubin, and inflammatory mediators such as cytokines. It has now been found that ASBT inhibitors may also play a key role in mediating the toxic effects of bile acids in the kidney. The inventors have observed that ASBT is strongly downregulated after bile duct ligation (BDL) in mice (see Figures 2 and 3), and inhibition of renal ASBT greatly improves cholestatic nephropathy in mice. Specifically, it has been found that the proximal tubular epithelial cells of the kidney are the cause of kidney disease because these cells accumulate bile acids through the transporter ASBT. It has been found that inhibition of ASBT almost completely inhibits the uptake of bile acids into the proximal tubular epithelial cells, thereby preventing bile casts and kidney disease. This is unexpected because ASBT is mainly expressed in the proximal tubules, while bile casts form in the distal tubules. Given that many mediators may be involved in the etiology of kidney disease, it is surprising that ASBT inhibitors have such a profound effect. The similarity of the histological key features and ASBT expression in the kidneys of patients with cholestatic nephropathy suggests a therapeutic prospect in humans. Thus, inhibition of ASBT may have a protective effect on the kidney, especially in cases where the patient also has advanced liver disease.

[0036] Accordingly, in a first aspect, the present invention relates to an ASBT inhibitor (such as any ASBT inhibitor described herein) or a pharmaceutically acceptable salt thereof for use in the treatment of a kidney disease or disorder. In some embodiments, the kidney disease or disorder is selected from cholestatic nephropathy, chronic kidney disease, hyperbilirubinemia, renal dysfunction in obstructive jaundice, age-induced impairment of renal mitochondrial function, renal inflammation, acute kidney injury (AKI), renal ischemia / reperfusion injury (IRI), chronic kidney disease (CKD), chronic renal insufficiency, end-stage renal disease (ESRD), renal proximal tubular injury, type 1 hepatorenal syndrome, type 2 hepatorenal syndrome, and acute-on-chronic liver disease.

[0037] In some embodiments, the kidney disease or disorder is a bile acid-dependent kidney disease or disorder, e.g., a kidney disease or disorder that may benefit from partial or complete inhibition of renal ASBT. Non-limiting examples of bile acid-dependent kidney diseases or disorders include cholestatic nephropathy, chronic kidney disease, hyperbilirubinemia, renal dysfunction in obstructive jaundice, age-induced impairment of renal mitochondrial function, renal inflammation, acute kidney injury (AKI), renal ischemia / reperfusion injury (IRI), chronic kidney disease (CKD), chronic renal insufficiency, end-stage renal disease (ESRD), renal proximal tubular injury, type 1 hepatorenal syndrome, type 2 hepatorenal syndrome, and acute-on-chronic liver disease.

[0038] In some embodiments, the present invention relates to an ASBT inhibitor (e.g., any ASBT inhibitor described herein) or a pharmaceutically acceptable salt thereof for the treatment of biliary nephropathy.

[0039] ASBT inhibitor

[0040] In some embodiments, the ASBT inhibitor is a compound disclosed in, for example, WO 93 / 16055, WO94 / 18183, WO 94 / 18184, WO 96 / 05188, WO 96 / 08484, WO 96 / 16051, WO 97 / 33882, WO 98 / 03818, WO 98 / 07449, WO 98 / 40375, WO 99 / 35135, WO 99 / 64409, WO 99 / 64410, WO 00 / 01687, WO 00 / 47568, WO 00 / 61568, WO 00 / 38725, WO 00 / 38726, WO 00 / 38727, WO 00 / 38728, WO 00 / 38729, WO 01 / 66533, WO 01 / 68096, WO 02 / 32428, WO 02 / 50051, WO 03 / 020710, WO 03 / 022286, WO 03 / 022825, WO 03 / 022830, WO 03 / 061663, WO 03 / 091232, WO03 / 106482, WO 2004 / 006899, WO 2004 / 076430, WO 2007 / 009655, WO 2007 / 009656, WO2008 / 058628, WO 2008 / 058630, WO 2011 / 137135, WO 2019 / 234077, WO 2020 / 161216, WO2020 / 161217, WO 2021 / 110884, WO 2021 / 110885, WO 2021 / 110886, WO 2021 / 110887, WO2022 / 029101, DE 19825804, EP 864582, EP 489423, EP 549967, EP 573848, EP 624593, EP624594, EP 624595, EP 624596, EP 0864582, EP 1173205, EP 1535913, EP 1719768 or EP3210977.

[0041] In some embodiments, the ASBT inhibitor is a compound of formula (I):

[0042] (I)

[0043] Wherein:

[0044] R v is selected from hydrogen or C 1-6 alkyl;

[0045] R 1 and R 2 one of which is selected from hydrogen, C 1-6 alkyl or C 2-6 alkenyl and the other is selected from C 1-6 alkyl or C 2-6 alkenyl;

[0046] R x and R y are independently selected from hydrogen, hydroxyl, amino, mercapto, C 1-6 alkyl, C 1-6 alkoxy, N-(C 1-6 alkyl)amino, N,N-(C 1-6 alkyl)2amino, C 1-6 alkylS(O) a , where a is from 0 to 2;

[0047] M is selected from -N- or -CH-;

[0048] R z is selected from halogen, nitro, cyano, hydroxyl, amino, carboxyl, carbamoyl, mercapto, sulphonylamino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N-(C 1-6 alkyl)amino, N,N-(C 1-6 alkyl)2amino, C 1-6 alkanoylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 alkyl)2carbamoyl, C 1-6 alkylS(O) a (where a is from 0 to 2), C 1-6 alkoxycarbonyl, N-(C 1-6 alkyl)sulphonylamino and N,N-(C 1-6 alkyl)2sulphonylamino);

[0049] v is 0 - 5;

[0050] R 4 and R5 One of them is a group of formula (IA):

[0051]

[0052] (IA)

[0053] R 3 and R 6 and further R 4 and R 5 and the other is independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyloxy, N-(C 1-4 alkyl)amino, N,N-(C 1-4 alkyl)2amino, C 1-4 alkanoylamino, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 alkyl)2carbamoyl, C 1-4 alkylS(O) a (where a is from 0 to 2), C 1-4 alkoxycarbonyl, N-(C 1-4 alkyl)sulfamoyl and N,N-(C 1-4 alkyl)2sulfamoyl; where R 3 and R 6 and further R 4 and R 5 and the other may optionally be substituted on carbon by one or more R 16 substituents;

[0054] X is -O-, -N(R a )-, -S(O) b - or -CH(R a )-; where R a is hydrogen or C 1-6 alkyl, and b is 0 - 2;

[0055] Ring A is aryl or heteroaryl; where ring A is optionally substituted by one or more substituents selected from R 17 ;

[0056] R 7 is hydrogen, C 1-4 alkyl, carbocyclic or heterocyclic; where R 7 is optionally substituted by one or more substituents selected from R 18 ;

[0057] R 8 is hydrogen or C 1-4 alkyl;

[0058] R 9 is hydrogen or C 1-4 alkyl;

[0059] R 10 is hydrogen, C 1-4 alkyl, a carbocyclic group or a heterocyclic group; wherein R 10 is optionally substituted by one or more substituents selected from R 19 ;

[0060] R 11 is a carboxyl group, a sulfo group, a sulphino group, a phosphonyl group, -P(O)(OR c )(OR d ), -P(O)(OH)(OR c ), -P(O)(OH)(R d ), or -P(O)(OR c )(R d ), wherein R c and R d are independently selected from C 1-6 alkyl; or R 11 is a group of formula (IB) or (IC):

[0061]

[0062] (IB)

[0063]

[0064] (IC)

[0065] wherein:

[0066] Y is -N(R n ), -N(R n )C(O)-, -N(R n )C(O)(CR s R t ) v N(R n )C(O)-, -O-, and -S(O)a-; where a is 0 - 2, v is 1 - 2, R s and R t are independently selected from hydrogen or C 26 alkyl optionally substituted by R 1-4 and R n is hydrogen or C 1-4 alkyl;

[0067] R 12 is hydrogen or C 1-4 alkyl;

[0068] R 13 and R 14 are independently selected from hydrogen, C 1-6 alkyl, carbocyclic group or heterocyclic group; and when q is 0, R 14 may additionally be selected from hydroxy; wherein R 13 and R 14 may independently and optionally be substituted by one or more substituents selected from R 20 ;

[0069] R 15 is carboxyl, sulfo, sulfino, phosphonyl, -P(O)(OR e )(OR f ), -P(O)(OH)(OR e ), -P(O)(OH)(R e ), or -P(O)(OR e )(R f ), wherein R e and R f are independently selected from C 1-6 alkyl;

[0070] p is 1 - 3; wherein the values of R 13 may be the same or different;

[0071] q is 0 - 1;

[0072] r is 0 - 3; wherein the values of R 14 may be the same or different;

[0073] m is 0 - 2; wherein the values of R 10 may be the same or different;

[0074] n is 1 - 3; wherein the values of R 7 may be the same or different;

[0075] Ring B is a nitrogen - linked heterocyclic group substituted on carbon by a group selected from R 23 and optionally further substituted on carbon by one or more R 24 ; and wherein if the nitrogen - linked heterocyclic group contains an -NH - moiety, the nitrogen may optionally be substituted by a group selected from R 25 ;

[0076] R 16 、R 17 and R 18 are independently selected from halogen, nitro, cyano, hydroxy, amino, carboxyl, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkanoyl, C 1-4 Alkanoyloxy, N-(C 1-4 Alkyl)amino, N,N-(C 1-4 Alkyl)2amino, C 1-4 Alkanoylamino, N-(C 1-4 Alkyl)aminocarbonyl, N,N-(C 1-4 Alkyl)2aminocarbonyl, C 1-4 AlkylS(O) a (where a is from 0 to 2), C 1-4 Alkoxycarbonyl, N-(C 1-4 Alkyl)sulfamoyl and N,N-(C 1-4 Alkyl)2sulfamoyl; where R 16 , R 17 and R 18 may independently and optionally be substituted on carbon by one or more R 21 substituents;

[0077] R 19 , R 20 , R 24 and R 26 are independently selected from halogen, nitro, cyano, hydroxy, amino, carboxy, aminocarbonyl, mercapto, sulfamoyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkanoyl, C 1-4 Alkanoyloxy, N-(C 1-4 Alkyl)amino, N,N-(C 1-4 Alkyl)2amino, C 1-4 Alkanoylamino, N-(C 1-4 Alkyl)aminocarbonyl, N,N-(C 1-4 Alkyl)2aminocarbonyl, C 1-4 AlkylS(O) a (where a is from 0 to 2), C 1-4 Alkoxycarbonyl, N-(C 1-4 Alkyl)sulfamoyl, N,N-(C 1-4 Alkyl)2sulfamoyl, carbocyclic group, heterocyclic group, benzyloxycarbonylamino, (C 1-4 Alkyl)3silyl, sulfo, sulfino, amidino, phosphoryl, -P(O)(OR a )(OR b ), -P(O)(OH)(OR a)、 -P(O)(OH)(R a ) or -P(O)(OR a )(R b ), wherein R a and R b are independently selected from C 1-6 alkyl; wherein R 19 , R 20 , R 24 and R 26 may independently and optionally be substituted on the carbon by one or more R 22 ;

[0078] R 21 and R 22 are independently selected from halogen, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, methanesulfonyl, N-methylsulfamoyl and N,N-dimethylsulfamoyl;

[0079] R 23 is carboxy, sulfo, sulfino, phosphonyl, -P(O)(OR g )(OR h ), -P(O)(OH)(OR g ), -P(O)(OH)(R g ), or -P(O)(OR g )(R h ), wherein R g and R h are independently selected from C 1-6 alkyl; and

[0080] R 25 is selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carbamoyl, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl;

[0081] or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the ASBT inhibitor is a compound of formula (II):

[0083] (II)

[0084] Wherein:

[0085] R v and R w are independently selected from hydrogen or C 1-6 alkyl;

[0086] R 1 and R 2 are independently selected from C 1-6 alkyl;

[0087] R x and R y are independently selected from hydrogen or C 1-6 alkyl, or one of R x and R y is hydrogen or C 1-6 alkyl, and the other is hydroxyl or C 1-6 alkoxy;

[0088] R z is selected from halogen, nitro, cyano, hydroxyl, amino, carboxyl, carbamoyl, mercapto, sulfamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N-(C 1-6 alkyl)amino, N,N-(C 1-6 alkyl)2amino, C 1-6 alkanoylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 alkyl)2carbamoyl, C 1-6 alkylS(O) a (where a is from 0 to 2), C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonylamino, ureido, N'-(C 1-6 alkyl)ureido, N-(C 1-6 alkyl)ureido, N',N'-(C 1-6 alkyl)2ureido, N'-(C 1-6 alkyl)-N-(C 1-6 alkyl)ureido, N',N'-(C 1-6 alkyl)2-N-(C 1-6 alkyl)ureido, N-(C 1-6 alkyl)sulfamoyl and N,N-(C 1-6 alkyl)2sulfamoyl;

[0089] v is from 0 to 5;

[0090] R 4 and R 5 one of them is a group of formula (IIA):

[0091]

[0092] (IIA)

[0093] R 3 and R 6 and also R 4 and R 5 the other is independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyloxy, N-(C 1-4 alkyl)amino, N,N-(C 1-4 alkyl)2amino, C 1-4 alkanoylamino, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 alkyl)2carbamoyl, C 1-4 alkylS(O) a (where a is from 0 to 2), C 1-4 alkoxycarbonyl, N-(C 1-4 alkyl)sulfamoyl and N,N-(C 1-4 alkyl)2sulfamoyl;

[0094] wherein R 3 and R 6 and also R 4 and R 5 the other may optionally be substituted on carbon by one or more R 16 substituents;

[0095] D is -O-, -N(R a )-, -S(O) b -, or -CH(R a )-; wherein R a is hydrogen or C 1-6 alkyl and b is from 0 to 2;

[0096] Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted by one or more substituents selected from R 17 ;

[0097] R7 is hydrogen, C 1-4 alkyl, carbocyclic group or heterocyclic group; wherein R 7 is optionally substituted by one or more substituents selected from R 18 ;

[0098] R 8 is hydrogen or C 1-4 alkyl;

[0099] R 9 is hydrogen or C 1-4 alkyl;

[0100] R 10 is hydrogen, C 1-4 alkyl, carbocyclic group or heterocyclic group; wherein R 10 is optionally substituted by one or more substituents selected from R 19 ;

[0101] R 11 is selected from carboxyl, sulfo, sulfino, phosphonyl, tetrazolyl, -P(O)(OR c )(OR d ), -P(O)(OH)(OR c ), -P(O)(OH)(R d ), and -P(O)(OR c )(R d ), wherein R c and R d are independently selected from C 1-6 alkyl; or R 11 is a group of formula (IIB):

[0102]

[0103] (IIB)

[0104] wherein:

[0105] X is -N(R q ), -N(R q )C(O)-, -O- or -S(O) a -; wherein a is 0 - 2 and R q is hydrogen or C 1-4 alkyl;

[0106] R 12 is hydrogen or C 1-4 alkyl;

[0107] R 13 and R 14 are independently selected from hydrogen, C 1-4 alkyl, carbocyclic group, heterocyclic group and R 23 ; wherein the C1-4 An alkyl group, a carbocyclic group or a heterocyclic group may each independently optionally be substituted by one or more substituents selected from R 20 ;

[0108] R 15 is selected from a carboxyl group, a sulfo group, a sulfino group, a phosphonyl group, a tetrazolyl group, -P(O)(OR e )(OR f ), -P(O)(OH)(OR e ), -P(O)(OH)(R e ), and -P(O)(OR e )(R f ), where R e and R f are each independently selected from C 1-6 alkyl; or R 15 is a group of formula (IIC):

[0109]

[0110] (IIC)

[0111] wherein:

[0112] R 24 is hydrogen or C 1-4 alkyl;

[0113] R 25 is selected from hydrogen, C 1-4 alkyl, a carbocyclic group, a heterocyclic group and R 27 ; wherein the C 1-4 alkyl, carbocyclic group or heterocyclic group may each independently optionally be substituted by one or more substituents selected from R 28 ;

[0114] R 26 is selected from a carboxyl group, a sulfo group, a sulfino group, a phosphonyl group, a tetrazolyl group, -P(O)(OR g )(OR h ), -P(O)(OH)(OR g ), -P(O)(OH)(R g ), and -P(O)(OR g )(R h ), where R g and R h are each independently selected from C 1-6 alkyl;

[0115] p is 1 - 3; where the values of R 13 may be the same or different;

[0116] q is 0 - 1;

[0117] r ranges from 0 to 3; where R 14 values can be the same or different;

[0118] m ranges from 0 to 2; where R 10 values can be the same or different;

[0119] n ranges from 1 to 3; where R 7 values can be the same or different;

[0120] z ranges from 0 to 3; where R 25 values can be the same or different;

[0121] R 16 、R 17 and R 18 are each independently selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyloxy, N-(C 1-4 alkyl)amino, N,N-(C 1-4 alkyl)2amino, C 1-4 alkanoylamino, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 alkyl)2carbamoyl, C 1-4 alkylS(O) a (where a ranges from 0 to 2), C 1-4 alkoxycarbonyl, N-(C 1-4 alkyl)sulfamoyl and N,N-(C 1-4 alkyl)2sulfamoyl;

[0122] where R 16 、R 17 and R 18 may each independently optionally be substituted on the carbon by one or more R 21 ;

[0123] R 19 、R 20 、R 23 、R 27 and R 28 are each independently selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkanoyl, C1-4 alkanoyloxy, N-(C 1-4 alkyl)amino, N,N-(C 1-4 alkyl)2amino, C 1-4 alkanoylamino, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 alkyl)2carbamoyl, C 1-4 alkylS(O) a (where a is from 0 to 2), C 1-4 alkoxycarbonyl, N-(C 1-4 alkyl)sulfamoyl, N,N-(C 1-4 alkyl)2sulfamoyl, carbocyclic group, heterocyclic group, sulfo group, sulfino group, amidino group, phosphoryl group, -P(O)(OR a )(OR b ), -P(O)(OH)(OR a ), -P(O)(OH)(R a ), or -P(O)(OR a )(R b ), where R a and R b are independently selected from C 1-6 alkyl; where R 19 , R 20 , R 23 , R 27 and R 28 may independently and optionally be substituted on carbon by one or more R 22 ; and

[0124] R 21 and R 22 are independently selected from halogen, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, methylsulfonyl, N-methylsulfamoyl, and N,N-dimethylsulfamoyl;

[0125] or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the ASBT inhibitor is a compound of formula (III):

[0127] (III)

[0128] Wherein:

[0129] q is an integer from 1 to 4;

[0130] n is an integer from 0 to 2;

[0131] R 1 and R 2 are independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,

[0132] wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl are optionally substituted with one or more substituents selected from: OR 9 , NR 9 R 10 , N + R 9 R 10 R w A - , SR 9 , S + R 9 R 10 A - . P + R 9 R 10 R 11 A - , S(O)R 9 , SO2R 9 , SO3R 9 , CO2R 9 , CN, halogen, oxo, and CONR 9 R 10 ,

[0133] wherein the alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl are optionally substituted with one or more O, NR 9 , N + R 9 R 10 A - , S, SO, SO2, S + R 9 A - , P + R 9 R 10 A - or a carbon substituted with phenylene,

[0134] wherein R 9 , R 10 and R windependently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocycloalkyl, and alkylammonium alkyl; or

[0135] R 1 and R 2 together with the carbon to which they are attached form a C 3-10 cycloalkyl;

[0136] R 3 and R 4 independently selected from H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 , NR 9 R 10 , SR 9 , S(O)R 9 , SO2R 9 and SO3R 9 , where R 9 and R 10 are as defined above; or

[0137] R 3 and R 4 together form =O, =NOR 11 , =S, =NNR 11 R 12 , =NR 9 or =CR 11 R 12 ,

[0138] where R 11 and R 12 independently selected from H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 , NR 9 R 10 , SR 9 , S(O)R 9 , SO2R 9 , SO3R 9 , CO2R 9 , CN, halogen, oxo, and CONR 9 R 10 , where R 9 and R 10 are as defined above, provided that R 3 and R 4 cannot both be OH, NH2, and SH, or

[0139] R11 and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

[0140] R 5 is an aryl group substituted by one or more OR 13a substituents;

[0141] wherein R 13a is selected from alkylarylalkyl, alkylheteroarylalkyl, alkylheterocycloalkyl, heterocycloalkyl, heteroarylalkyl, quaternary heterocycloalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl,

[0142] R 13a is optionally substituted by one or more groups selected from: hydroxyl, amino, sulfo, carboxyl, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocycloalkyl, quaternary heteroarylalkyl, guanidino, OR 9 , NR 9 R 10 , N + R 9 R 11 R 12 A - , SR 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR 9 R 10 , SO2OM, SO2NR 9 R 10 , PO(OR 16 )OR 17 , P + R 9 R 10 R 11 A - , S + R 9 R 10 A - and C(O)OM,

[0143] wherein A - is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation, wherein R 16 and R 17 are independently selected from the substituents that make up R 9 and M; and

[0144] R 6 is selected from H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR 30, SR 9 , S(O)R 9 , SO2R 9 and SO3R 9 ,

[0145] wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle and quaternary heteroaryl can be substituted by one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13 , NR 13 R 14 , SR 13 , S(O)R 13 , SO2R 13 , SO3R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, COR 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 CO2R 14 , OC(O)R 13 , OC(O)NR 13 R 14 , NR 13 SOR 14 , NR 13 SO2R 14 , NR 13 SONR 14 R 15 , NR 13 SO2NR 14 R 15 , P(O)R 13 R 14 , P + R 13 R 14 R 15 A - , P(OR 13 )OR 14 , S +R 13 R 14 A - and N + R 9 R 11 R 12 A - , wherein:

[0146] A - is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation,

[0147] The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may be further substituted by one or more substituents selected from: OR 7 、NR 7 R 8 、SR 7 、S(O)R 7 、SO2R 7 、SO3R 7 、CO2R 7 、CN, oxo, CONR 7 R 8 、N + R 7 R 8 R 9 A - 、alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 、P + R 7 R 8 R 9 A - and P(O)(OR 7 )OR 8 , and

[0148] wherein the alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may optionally have one or more carbons replaced by: O, NR 7 、N + R 7 R 8 A - 、S, SO, SO2, S + R 7 A - 、PR 7 、P(O)R 7 、P + R 7 R 8 A - or phenylene, and R 13, R 14 and R 15 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocycloalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocycloalkylalkyl, heteroarylalkyl, quaternary heterocycloalkylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl,

[0149] wherein the alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by the following: O, NR 9 , N + R 9 R 10 A - , S, SO, SO2, S + R 9 A - , PR 9 , P + R 9 R 10 A - , P(O)R 9 , phenylene, carbohydrate, amino acid, peptide, or polypeptide, and

[0150] R 13 , R 14 and R 15 are optionally substituted with one or more groups selected from the following: hydroxyl, amino, sulfo, carboxyl, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocycloalkylalkyl, quaternary heteroarylalkyl, guanidyl, OR 9 , NR 9 R 10 , N + R 9 R 11 R 12 A - , SR 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR 9 R 10 , SO2OM, SO2NR 9 R 10 , PO(OR 16 )OR 17 , P + R 9 R 10 R 11 A - , S+ R 9 R 10 A - and C(O)OM,

[0151] wherein R 16 and R 17 are independently selected from the substituents that constitute R 9 and M; or

[0152] R 13 and R 14 together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle, which monocyclic or polycyclic heterocycle is optionally substituted by one or more groups selected from oxo, carboxyl, and quaternary salts; or

[0153] R 14 and R 15 together with the nitrogen atom to which they are attached form a cyclic ring; and

[0154] R 30 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonium alkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, alkoxycarbonylalkyl, carboxyalkylamino, heteroarylalkyl, heterocycloalkyl, and alkylammonium alkyl; and

[0155] R 7 and R 8 are independently selected from hydrogen and alkyl; and

[0156] one or more R x are independently selected from H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR 13 、NR 13 R 14 、SR 13 、S(O)R 13 、S(O)2R 13 、SO3R 13 、S + R 13 R 14 A - 、NR 13 OR 14 、NR 13 NR 14 R 15 、NO2、CO2R 13 、CN、OM、SO2OM、SO2NR 13 R 14 、NR 14 C(O)R 13 、C(O)NR13 R 14 、 NR 14 C(O)R 13 、 C(O)OM、 COR 13 、 OR 18 、 S(O) n NR 18 、 NR 13 R 18 、 NR 18 OR 14 、 N + R 9 R 11 R 12 A - 、 P + R 9 R 11 R 12 A - 、 amino acids, peptides, polypeptides and carbohydrates,

[0157] wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle and quaternary heteroaryl may be further substituted by: OR 9 、 NR 9 R 10 、 N + R 9 R 11 R 12 A - 、 SR 9 、 S(O)R 9 、 SO2R 9 、 SO3R 9 、 oxo, CO2R 9 、 CN, halogen, CONR 9 R 10 、 SO2OM, SO2NR 9 R 10 、 PO(OR 16 )OR 17 、 P + R 9 R 11 R 12 A - 、 S + R 9 R 10 A - or C(O)OM, and

[0158] wherein R 18 is selected from acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

[0159] Wherein the acyl group, arylalkoxycarbonyl group, arylalkyl group, heterocycle, heteroaryl group, alkyl group, quaternary heterocycle and quaternary heteroaryl group are optionally substituted by one or more substituents selected from the following: OR 9 , NR 9 R 10 , N + R 9 R 11 R 12 A - , SR 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR 9 R 10 , SO3R 9 , SO2OM, SO2NR 9 R 10 , PO(OR 16 )OR 17 and C(O)OM,

[0160] wherein in R x , one or more carbons are optionally replaced by the following: O, NR 13 , N + R 13 R 14 A - , S, SO, SO2, S + R 13 A - , PR 13 , P(O)R 13 , P + R 13 R 14 A - , phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether or polyalkyl,

[0161] wherein in the polyalkyl, phenylene, amino acid, peptide, polypeptide and carbohydrate, one or more carbons are optionally replaced by the following: O, NR 9 , N + R 9 R 10 A - , S, SO, SO2, S + R 9 A - , PR 9 , P + R 9 R 10 A - or P(O)R 9 ;

[0162] wherein the quaternary heterocycle and quaternary heteroaryl are optionally substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 , NR 13 R 14 , SR 13 , S(O)R 13 , SO2R 13 , SO3R 13 , NR 13 OR 14 , NR 13 , NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, COR 13 , P(O)R 13 R 14 , P + R 13 R 14 R 15 A - , P(OR 13 )OR 14 , S + R 13 R 14 A - and N + R 9 R 11 R 12 A - ;

[0163] or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the ASBT inhibitor is a compound of formula (IV):

[0165] (IV)

[0166] wherein

[0167] X is O, NH, CH2 or a bond;

[0168] R 1 is C 1-6 alkyl;

[0169] R 2 , R 2’ , R3 , R 3’ , R 4 , R 4’ , R 5 and R 5’ are each independently selected from H, Cl, Br, I, OH, -(CH2)-OH, CF3, NO2, N3, CN, S(O) p -R 6 , O-S(O) p -R 6 , C 1-6 alkylene-S(O) p -R 6 , C 1-6 alkylene-O-S(O) p -R 6 , COOH, COOC 1-6 alkyl, CONH2, CONHC 1-6 alkyl, CON(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and O-C 1-6 alkyl, wherein one or more alkyl hydrogens may be replaced by fluorine; and phenyl, -(CH2)-phenyl, -(CH2) n -phenyl, O-phenyl, O-(CH2) m -phenyl, -(CH2)-O-(CH2) m -phenyl, wherein the phenyl ring may be substituted one to three times by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-C 1-6 alkyl, C 1-6 alkyl, NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, SO2-CH3, COOH, COOC 1-6 alkyl or CONH2;

[0170] wherein at least one of R 2 , R 2’ , R 3 , R 3’ , R 4 , R 4’ , R 5 , R 5’ is always at least one of -O-(CH2) m -phenyl or -(CH2)-O-(CH2) m -phenyl, wherein the phenyl ring may be substituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-C 1-6 alkyl, C1-6 alkyl, NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, SO2-CH3, COOH, COOC 1-6 alkyl, CONH2 substituted one to 3 times;

[0171] R 6 selected from H, OH, C 1-6 alkyl, NH2, NHC 1-6 alkyl and N(C 1-6 alkyl)2;

[0172] n is an integer 2, 3, 4, 5 or 6;

[0173] m is an integer 1, 2, 3, 4, 5 or 6; and

[0174] p is an integer 0, 1 or 2;

[0175] or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the ASBT inhibitor is a compound of formula (V):

[0177] (V)

[0178] wherein

[0179] R 1 is selected from H, Cl, Br, N(CH3)2 and methoxy;

[0180] R 2 is H or OH;

[0181] each R 3 is independently C 1-6 alkyl;

[0182] X is CH2, C(O) or CH=CH;

[0183] Q is C 0-6 alkyl;

[0184] R 4 is selected from OH, SO3H, CO2H, PO3H2, CONR 5 R 5 , NR 5 R 5 and NHC(O)CH2NR 5 R 5 ;

[0185] each R 5 is independently selected from H, OH, C 1-6 alkyl, C 0-6Alkyl CO2H, C 0-6 Alkyl SO3H, C 0-6 Alkyl PO3H2, C(O)C 0-6 Alkyl CO2H, C(O)C 0-6 Alkyl SO3H, C(O)C 0-6 Alkyl PO3H2 and CH(R 6 )C 0-6 Alkyl CO2H; and

[0186] R 6 is selected from C 0-6 Alkyl CO2H, C 0-6 Alkyl OH, C 0-6 Alkyl SO3H and C 0-6 Alkyl PO3H2;

[0187] or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the ASBT inhibitor is a compound of formula (VI):

[0189] (VI)

[0190] wherein

[0191] M is selected from -CH2- and -NR 7 -;

[0192] R 1 and R 2 are each independently C 1-4 alkyl;

[0193] R 3 is selected from hydrogen, halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, cyano, nitro, amino, N-(C 1-4 alkyl)amino, N,N-bis(C 1-4 alkyl)amino, N-(aryl-C 1-4 alkyl)amino, C 1-6 alkylcarbonylamino, C 3-6 cycloalkylcarbonylamino, N-(C 1-4 alkyl)aminocarbonyl, N,N-bis(C 1-4 alkyl)aminocarbonyl, C 1-4 alkoxycarbonylamino, C 3-6 cycloalkyloxycarbonylamino, C 1-4 alkylsulfonylamino and C 3-6 cycloalkylsulfonylamino;

[0194] n is an integer 1, 2 or 3;

[0195] R 4 selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 1-4 alkylthio, C 3-6 cycloalkylthio, amino, N-(C 1-4 alkyl)amino, and N,N-di(C 1-4 alkyl)amino;

[0196] R 5 and R 6 one of which is a carboxyl group, and R 5 and R 6 the other of which is selected from hydrogen, fluorine, C 1-4 alkyl, and C 1-4 haloalkyl;

[0197] R 7 is selected from hydrogen and C 1-4 alkyl; and

[0198] R 8 is selected from hydrogen and C 1-4 alkyl;

[0199] or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the ASBT inhibitor is a compound of formula (VII):

[0201] (VII)

[0202] wherein

[0203] M is -CH2- or -NR 6 -;

[0204] R 1 and R 2 are each independently C 1-4 alkyl;

[0205] R 3 is independently selected from hydrogen, halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, cyano, nitro, amino, N-(C 1-4 alkyl)amino, N,N-di(C 1-4 alkyl)amino, and N-(aryl-C 1-4 alkyl)amino;

[0206] n is an integer 1, 2 or 3;

[0207] R 4 is selected from hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 1-4 alkylthio, C 3-6 cycloalkylthio, amino, N-(C 1-4 alkyl)amino and N,N-di(C 1-4 alkyl)amino; and

[0208] R 5A , R 5B , R 5C and R 5D are each independently selected from hydrogen, halogen, hydroxy, amino, C 1-4 alkyl and C 1-4 alkoxy; and

[0209] R 6 is selected from hydrogen and C 1-4 alkyl;

[0210] or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the ASBT inhibitor is a compound of formula (VIII):

[0212] (VIII)

[0213] wherein

[0214] M is -CH2- or -NH-;

[0215] R 1 and R 2 are each independently C 1-4 alkyl;

[0216] R 3 is independently selected from hydrogen, halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, cyano, nitro, amino, N-(C 1-4 alkyl)amino, N,N-di(C 1-4 alkyl)amino and N-(aryl-C 1-4 alkyl)amino;

[0217] n is an integer 1, 2 or 3; and

[0218] R4 Selected from hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 1-4 alkylthio, C 3-6 cycloalkylthio, amino, N-(C 1-4 alkyl)amino and N,N-di(C 1-4 alkyl)amino;

[0219] or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the ASBT inhibitor is a compound of formula (IX):

[0221] (IX)

[0222] wherein

[0223] M is selected from -CH2- and -NR 6 -;

[0224] R 1 is C 1-4 alkyl;

[0225] R 2 is independently selected from hydrogen, halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, cyano, nitro, amino, N-(C 1-4 alkyl)amino, N,N-di(C 1-4 alkyl)amino, N-(aryl-C 1-4 alkyl)amino, C 1-6 alkylcarbonylamino, C 3-6 cycloalkylcarbonylamino, N-(C 1-4 alkyl)aminocarbonyl, N,N-di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkyloxycarbonylamino, C 3-6 cycloalkyloxycarbonylamino, C 1-4 alkylsulfonylamino and C 3-6 cycloalkylsulfonylamino;

[0226] n is an integer of 1, 2 or 3;

[0227] R 3 is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyloxy, C1-4 alkylthio, C 3-6 cycloalkylthio, amino, N-(C 1-4 alkyl)amino, and N,N-di(C 1-4 alkyl)amino;

[0228] R 4 and R 5 one of which is a carboxyl group, and R 4 and R 5 the other is selected from hydrogen, fluorine, C 1-4 alkyl, and C 1-4 haloalkyl;

[0229] R 6 is selected from hydrogen and C 1-4 alkyl; and

[0230] R 7 is selected from hydrogen and C 1-4 alkyl;

[0231] or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the ASBT inhibitor is a compound of formula (X):

[0233] (X)

[0234] wherein

[0235] M is -CH2- or -NR 6 -;

[0236] R 1 is C 1-4 alkyl;

[0237] R 2 is selected from hydrogen and C 1-4 alkyl;

[0238] R 3 is independently selected from hydrogen, halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, cyano, nitro, amino, N-(C 1-4 alkyl)amino, and N,N-di(C 1-4 alkyl)amino;

[0239] n is an integer of 1, 2, or 3;

[0240] R 4 is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4Alkoxy, C 3-6 Cycloalkyloxy, C 1-4 Alkylthio, C 3-6 Cycloalkylthio, amino, N-(C 1-4 alkyl)amino and N,N-di(C 1-4 alkyl)amino;

[0241] R 5A and R 5B each independently selected from hydrogen, halogen, hydroxy, C 1-4 alkyl and C 1-4 alkoxy; or R 5A and R 5B together with the carbon atom to which they are attached form a 3- to 5-membered saturated carbocyclic ring; and

[0242] R 6 is selected from hydrogen and C 1-4 alkyl;

[0243] or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the ASBT inhibitor is a compound selected from:

[0245] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

[0246] 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

[0247] 1-{ [4-({4-[(4R,5R)-3,3-Dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ 6 -benzothiazepin-5-yl]phenoxy}methyl)phenyl]methyl}-1,4-diazabicyclo[2.2.2]oct-1-ium chloride;

[0248] N-(3-O-Benzyl-6-O-sulfo-β-D-glucopyranosyl)-N'-{3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ 6 -benzothiazepin-5-yl]phenyl}urea;

[0249] 3-({[(3R,5R)-3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1H-1λ 6 ,4-benzothiazepine-8-yl]methyl}amino)pentanedioic acid;

[0250] (Z)-3-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)-2-fluoroacrylic acid;

[0251] (Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)-2-fluoroacrylic acid;

[0252] 3-((7-bromo-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)propanoic acid;

[0253] 3-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)-2-hydroxypropanoic acid;

[0254] 3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)propanoic acid;

[0255] 3-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)propanoic acid;

[0256] 3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)propanoic acid;

[0257] 2-((3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)acetic acid;

[0258] 2-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo-1,2,5-thiadiazepin-8-yl)oxy)acetic acid; and

[0259] (E)-3-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acrylic acid;

[0260] or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, the ASBT inhibitor is (Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid:

[0262]

[0263] or a pharmaceutically acceptable salt thereof, also referred to herein as "Compound 1". In some embodiments, the ASBT inhibitor is (S)-(Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is (S)-(Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid. In some embodiments, the ASBT inhibitor is (R)-(Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is (R)-(Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid. Compound 1 can be prepared as described in WO 2019 / 234077.

[0264] In some embodiments, the ASBT inhibitor is 3-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)propanoic acid:

[0265]

[0266] or a pharmaceutically acceptable salt thereof, also referred to herein as "Compound 2". Compound 2 can be prepared as described in WO 2020 / 161217.

[0267] In some embodiments, the ASBT inhibitor is 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid:

[0268]

[0269] or a pharmaceutically acceptable salt thereof, also referred to herein as "Compound 3". In some embodiments, the ASBT inhibitor is (S)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 3 is (S)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid. In some embodiments, the ASBT inhibitor is (R)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 3 is (R)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid. Compound 2 can be prepared as described in PCT / EP2023 / 068476.

[0270] In some embodiments, the ASBT inhibitor is 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid:

[0271]

[0272] or a pharmaceutically acceptable salt thereof, also referred to herein as "Compound 4". In some embodiments, the ASBTI inhibitor is (S)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 4 is (S)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid. In some embodiments, the ASBTI inhibitor is (R)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 4 is (R)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid. Compound 4 can be prepared as described in PCT / EP2023 / 068476.

[0273] In some embodiments, the ASBT inhibitor is 2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)acetic acid:

[0274]

[0275] or a pharmaceutically acceptable salt thereof, also referred to herein as "Compound 5". In some embodiments, the ASBTI inhibitor is (S)-2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 5 is (S)-2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid. In some embodiments, the ASBTI inhibitor is (R)-2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 5 is (R)-2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid. Compound 5 can be prepared as described in WO 2021 / 110887.

[0276] In some embodiments, the ASBT inhibitor is a compound selected from the following:

[0277] (elobixibat);

[0278] (odevixibat);

[0279] (maralixibat);

[0280] (volixibat); and

[0281] (linerixibat);

[0282] or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the ASBT inhibitor is elobixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is obetixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is maribixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is volixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is linerixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor comprises a combination of two or more of elobixibat, obetixibat, maribixibat, volixibat, and linerixibat or a pharmaceutically acceptable salt thereof.

[0284] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0285] As used herein, the term "C 1-6 alkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and the term "C 1-4 alkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. Examples of C 1-4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0286] As used herein, the term "C 1-4 haloalkyl" refers to a straight-chain or branched-chain C 1-4 alkyl as defined herein, wherein one or more hydrogen atoms are replaced by a halogen. Examples of C 1-4 haloalkyl include chloromethyl, fluoroethyl, and trifluoromethyl.

[0287] As used herein, the terms "C 1-4 alkoxy" and "C 1-4 alkylthio" refer to a straight-chain or branched-chain C 1-4 alkyl group attached to the remainder of the molecule through an oxygen or sulfur atom, respectively.

[0288] As used herein, the term "C 3-6 cycloalkyl" refers to a monocyclic saturated hydrocarbon ring having 3 to 6 carbon atoms. Examples of C 3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0289] The term "amino" refers to the -NH2 group. As used herein, the terms "N-(C 1-4 alkyl)amino" and "N,N-di(C 1-4 alkyl)amino" refer to an amino group in which one or two hydrogen atoms are replaced by a straight-chain or branched-chain C 1-4 alkyl group, respectively. N-(C 1-4Examples of (Calkyl)amino include methylamino, ethylamino, and tert-butylamino, and N,N-di-(C 1-4 Examples of (Calkyl)amino include dimethylamino and diethylamino.

[0290] The term "aryl" refers to an aromatic monocyclic ring consisting of 6 carbon atoms or an aromatic bicyclic system consisting of 10 carbon atoms. Examples of aryl include phenyl, naphthyl, and azulenyl.

[0291] As used herein, the term "N-(aryl-C 1-4 alkyl)amino" refers to an amino group in which a hydrogen atom is replaced by an aryl-C 1-4 alkyl group. Examples of N-(aryl-C 1-4 alkyl)amino include benzylamino and phenylethylamino. The term "C 1-6 alkylcarbonylamino" refers to an amino group in which a hydrogen atom is replaced by a C 1-6 alkylcarbonyl group. Examples of C 1-6 alkanoylamino include acetylamino and tert-butylcarbonylamino. The term "C 1-4 alkyloxycarbonylamino" refers to an amino group in which a hydrogen atom is replaced by a C 1-4 alkyloxycarbonyl group. Examples of C 1-4 alkyloxycarbonylamino include tert-butoxycarbonylamino. The terms "C 1-4 alkylsulfonylamino" and "C 3-6 cycloalkylsulfonylamino" refer to amino groups in which a hydrogen atom is replaced by a C 1-4 alkylsulfonyl or a C 3-6 cycloalkylsulfonyl group, respectively.

[0292] Some ASBT inhibitors or their pharmaceutically acceptable salts may have chiral centers and / or geometric isomeric centers (E-isomers and Z-isomers). It should be understood that the present invention encompasses all such optical isomers, diastereoisomers, and geometric isomers having ASBT inhibitory activity. The present invention also encompasses any and all tautomeric forms having ASBT inhibitory activity. Certain ASBT inhibitors or their pharmaceutically acceptable salts may exist in non-solvated forms as well as solvated forms, such as hydrate forms. It should be understood that the present invention encompasses all such solvated forms having ASBT inhibitory activity.

[0293] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in human pharmaceutical applications and are generally safe, non-toxic, and without biological or other adverse effects.

[0294] Suitable pharmaceutically acceptable salts of the ASBT inhibitor are, for example, base addition salts of such compounds having sufficient acidity, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts formed with organic bases that provide physiologically acceptable cations, such as salts formed with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0295] Administration of the ASBT inhibitor

[0296] In some embodiments, after administration of the ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in serum bile acid concentration of at least 50% (e.g., at least 55%; at least 60%; at least 65%; at least 70%; at least 75%; at least 80%; at least 85%; at least 90%; or at least 95%) relative to baseline. In some embodiments, the subject exhibits a reduction in serum bile acid concentration of at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0297] In some embodiments, after administration of the ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in serum bile acid concentration of from about 50% to about 100% (e.g., from about 50% to about 60%; from about 50% to about 70%; from about 50% to about 80%; from about 50% to about 90%; from about 60% to about 70%; from about 60% to about 80%; from about 60% to about 90%; from about 60% to about 100%; from about 70% to about 80%; from about 70% to about 90%; from about 70% to about 100%; from about 80% to about 90%; from about 80% to about 100%; or from about 90% to about 100%) relative to baseline. In some embodiments, the subject exhibits a reduction in serum bile acid concentration of about 50%, about 60%, about 70%, about 80%, or about 90% relative to baseline.

[0298] In some embodiments, after administration of the ASBT inhibitor or a pharmaceutically acceptable salt thereof, the serum bile acid concentration normalizes. In some embodiments, the serum bile acid concentration normalizes after administration of the ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc.

[0299] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for about 1 week to about 72 weeks (e.g., about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 16 weeks, about 8 weeks to about 24 weeks, about 8 weeks to about 36 weeks, about 8 weeks to about 48 weeks, about 8 weeks to about 60 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 52 weeks, about 12 weeks to about 72 weeks, about 16 weeks to about 24 weeks, about 16 weeks to about 36 weeks, about 16 weeks to about 48 weeks, about 16 weeks to about 60 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 72 weeks, about 24 weeks to about 36 weeks, about 24 weeks to about 48 weeks, about 24 weeks to about 60 weeks, about 28 weeks to about 40 weeks, about 28 weeks to about 52 weeks, about 28 weeks to about 72 weeks, about 36 weeks to about 48 weeks, about 36 weeks to about 60 weeks, about 40 weeks to about 44 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks), the serum bile acid concentration normalizes.

[0300] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits at least a 50% increase in urinary bile acids relative to baseline (e.g., at least 55%; at least 60%; at least 65%; at least 70%; at least 75%; at least 80%; at least 85%; at least 90%; or at least 95%). In some embodiments, the subject exhibits at least a 60%, at least a 70%, at least an 80%, or at least a 90% increase in urinary bile acids relative to baseline.

[0301] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in urinary bile acids of about 50% to about 100% relative to baseline (e.g., about 50% to about 60%; about 50% to about 70%; about 50% to about 80%; about 50% to about 90%; about 60% to about 70%; about 60% to about 80%; about 60% to about 90%; about 60% to about 100%; about 70% to about 80%; about 70% to about 90%; about 70% to about 100%; about 80% to about 90%; about 80% to about 100%; or about 90% to about 100%). In some embodiments, the subject exhibits an increase in urinary bile acids of about 50%, about 60%, about 70%, about 80%, or about 90% relative to baseline.

[0302] In some embodiments, the presence of the diseases described herein (such as biliary nephropathy) is determined by one or more biomarkers indicating one or more of biliary obstruction, cholestasis, inflammation, hepatic fibrosis, cirrhosis, and / or their scoring systems. In some embodiments, the severity of the diseases described herein (such as biliary nephropathy) is determined by one or more biomarkers indicating one or more of biliary obstruction, cholestasis, inflammation, hepatic fibrosis, cirrhosis, and / or their scoring systems. In some embodiments, the treatment outcome of the diseases described herein (such as biliary nephropathy) is determined by one or more biomarkers indicating one or more of biliary obstruction, cholestasis, inflammation, hepatic fibrosis, cirrhosis, and / or their scoring systems. Non-limiting examples of biomarkers indicating one or more of biliary obstruction, cholestasis, inflammation, hepatic fibrosis, cirrhosis, and / or their scoring systems include the levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), serum bilirubin, prothrombin time (PT), international normalized ratio (INR), total protein, and albumin (see, e.g., Lala et al., “Liver Function Tests.” StatPearls, StatPearls Publishing, October 5, 2022 (PMID: 29494096, which is incorporated herein by reference in its entirety). In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits improvement in liver parameters (biomarkers). In some embodiments, the level of aspartate aminotransferase (AST) does not increase. In some embodiments, the level of aspartate aminotransferase (AST) decreases. In some embodiments, the level of alanine transaminase (ALT) does not increase. In some embodiments, the level of alanine transaminase (ALT) decreases. In some embodiments, the “level” of an enzyme refers to, for example, the concentration of the enzyme in the blood. For example, the level of AST or ALT can be expressed as units / L.

[0303] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the total serum bilirubin level is reduced. In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc., the total bilirubin level is reduced by about 0.5 mg / dL to about 5.0 mg / dL, about 1 mg / dL to about 5.0 mg / dL, about 1.5 mg / dL to about 5.0 mg / dL, or about 2.0 mg / dL to about 5.0 mg / dL relative to the baseline. For example, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks, the total bilirubin can be reduced by at least 70% (e.g., about 99%).

[0304] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the total bilirubin level is reduced by about 0.5 mg / dL to about 5.0 mg / dL, about 0.5 mg / dL to about 4.0 mg / dL, about 0.5 mg / dL to about 3.0 mg / dL, about 0.5 mg / dL to about 2.0 mg / dL, about 0.5 mg / dL to about 1.5 mg / dL, about 1.0 mg / dL to about 5.0 mg / dL, about 1.0 mg / dL to about 4.0 mg / dL, about 1.0 mg / dL to about 3.0 mg / dL, about 1.0 mg / dL to about 2.0 mg / dL, about 1.0 mg / dL to about 1.5 mg / dL, about 1.5 mg / dL to about 5.0 mg / dL, about 1.5 mg / dL to about 4.0 mg / dL, about 1.5 mg / dL to about 3.0 mg / dL, about 1.5 mg / dL to about 2.0 mg / dL, about 2.0 mg / dL to about 5.0 mg / dL, about 2.0 mg / dL to about 4.0 mg / dL, about 2.0 mg / dL to about 3.0 mg / dL, about 3.0 mg / dL to about 5.0 mg / dL, about 3.0 mg / dL to about 4.0 mg / dL, or about 4.0 mg / dL to about 5.0 mg / dL relative to baseline. For example, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the total bilirubin can be reduced by about 50% to about 100% (e.g., about 50% to about 60%; about 50% to about 70%; about 50% to about 80%; about 50% to about 90%; about 60% to about 70%; about 60% to about 80%; about 60% to about 90%; about 60% to about 100%; about 70% to about 80%; about 70% to about 90%; about 70% to about 100%; about 80% to about 90%; about 80% to about 100%; or about 90% to about 100%). In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the serum total bilirubin level is reduced by about 50%, about 60%, about 70%, about 80%, or about 90% relative to baseline.In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for about 1 week to about 72 weeks (e.g., about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 16 weeks, about 8 weeks to about 24 weeks, about 8 weeks to about 36 weeks, about 8 weeks to about 48 weeks, about 8 weeks to about 60 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 52 weeks, about 12 weeks to about 72 weeks, about 16 weeks to about 24 weeks, about 16 weeks to about 36 weeks, about 16 weeks to about 48 weeks, about 16 weeks to about 60 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 72 weeks, about 24 weeks to about 36 weeks, about 24 weeks to about 48 weeks, about 24 weeks to about 60 weeks, about 28 weeks to about 40 weeks, about 28 weeks to about 52 weeks, about 28 weeks to about 72 weeks, about 36 weeks to about 48 weeks, about 36 weeks to about 60 weeks, about 40 weeks to about 44 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks), the serum total bilirubin level is decreased. For example, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the total bilirubin can be decreased by about 50% to about 100% (e.g., about 50% to about 60%; about 50% to about 70%; about 50% to about 80%; about 50% to about 90%; about 60% to about 70%; about 60% to about 80%; about 60% to about 90%; about 60% to about 100%; about 70% to about 80%; about 70% to about 90%; about 70% to about 100%; about 80% to about 90%; about 80% to about 100%; or about 90% to about 100%).

[0305] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the serum alkaline phosphatase (ALP) level is improved. In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the ALP level is decreased. In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc., the ALP level is decreased by about 50 U / L to about 175 U / L, about 50 U / L to about 150 U / L, about 50 U / L to about 125 U / L, or about 100 U / L to about 150 U / L relative to the baseline. For example, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks, the ALP level can be decreased by about 50%, about 60% or about 70%.

[0306] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for about 1 week to about 72 weeks (e.g., about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 16 weeks, about 8 weeks to about 24 weeks, about 8 weeks to about 36 weeks, about 8 weeks to about 48 weeks, about 8 weeks to about 60 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 52 weeks, about 12 weeks to about 72 weeks, about 16 weeks to about 24 weeks, about 16 weeks to about 36 weeks, about 16 weeks to about 48 weeks, about 16 weeks to about 60 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 72 weeks, about 24 weeks to about 36 weeks, about 24 weeks to about 48 weeks, about 24 weeks to about 60 weeks, about 28 weeks to about 40 weeks, about 28 weeks to about 52 weeks, about 28 weeks to about 72 weeks, about 36 weeks to about 48 weeks, about 36 weeks to about 60 weeks, about 40 weeks to about 44 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks), the ALP level is reduced by about 50 U / L to about 175 U / L, about 50 U / L to about 150 U / L, about 50 U / L to about 125 U / L, about 50 U / L to about 75 U / L, about 75 U / L to about 175 U / L, about 75 U / L to about 150 U / L, about 75 U / L to about 125 U / L, about 75 U / L to about 100 U / L, about 100 U / L to about 175 U / L, about 100 U / L to about 150 U / L, about 100 U / L to about 125 U / L, or about 150 U / L to about 175 U / L relative to the baseline. For example, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the ALP level may be reduced by about 50%, about 60% or about 70%.

[0307] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the serum alanine aminotransferase (ALT) level is improved. In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the ALT level is decreased. In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc., the ALT level is decreased by about 50 U / L to about 175 U / L, about 50 U / L to about 150 U / L, about 50 U / L to about 125 U / L, or about 100 U / L to about 150 U / L relative to the baseline. For example, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks, the ALT level can be decreased by about 50%, about 60% or about 70%.

[0308] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the serum aspartate aminotransferase (AST) level is improved.

[0309] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for about 1 week to about 72 weeks (e.g., about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 16 weeks, about 8 weeks to about 24 weeks, about 8 weeks to about 36 weeks, about 8 weeks to about 48 weeks, about 8 weeks to about 60 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 52 weeks, about 12 weeks to about 72 weeks, about 16 weeks to about 24 weeks, about 16 weeks to about 36 weeks, about 16 weeks to about 48 weeks, about 16 weeks to about 60 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 72 weeks, about 24 weeks to about 36 weeks, about 24 weeks to about 48 weeks, about 24 weeks to about 60 weeks, about 28 weeks to about 40 weeks, about 28 weeks to about 52 weeks, about 28 weeks to about 72 weeks, about 36 weeks to about 48 weeks, about 36 weeks to about 60 weeks, about 40 weeks to about 44 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks), the ALT level is reduced by about 50 U / L to about 175 U / L, about 50 U / L to about 150 U / L, about 50 U / L to about 125 U / L, about 50 U / L to about 75 U / L, about 75 U / L to about 175 U / L, about 75 U / L to about 150 U / L, about 75 U / L to about 125 U / L, about 75 U / L to about 100 U / L, about 100 U / L to about 175 U / L, about 100 U / L to about 150 U / L, about 100 U / L to about 125 U / L, or about 150 U / L to about 175 U / L relative to the baseline. For example, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the ALT level may be reduced by about 50%, about 60%, or about 70%.

[0310] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in serum blood urea nitrogen (BUN). In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc., the BUN level is decreased by about 0.5 mg / dL to about 5.0 mg / dL, about 1 mg / dL to about 5.0 mg / dL, about 1.5 mg / dL to about 5.0 mg / dL, or about 2.0 mg / dL to about 5.0 mg / dL relative to the baseline. For example, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks, the BUN level can be decreased by about 50%, about 60% or about 70%.

[0311] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for about 1 week to about 72 weeks (e.g., about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 16 weeks, about 8 weeks to about 24 weeks, about 8 weeks to about 36 weeks, about 8 weeks to about 48 weeks, about 8 weeks to about 60 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 52 weeks, about 12 weeks to about 72 weeks, about 16 weeks to about 24 weeks, about 16 weeks to about 36 weeks, about 16 weeks to about 48 weeks, about 16 weeks to about 60 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 72 weeks, about 24 weeks to about 36 weeks, about 24 weeks to about 48 weeks, about 24 weeks to about 60 weeks, about 28 weeks to about 40 weeks, about 28 weeks to about 52 weeks, about 28 weeks to about 72 weeks, about 36 weeks to about 48 weeks, about 36 weeks to about 60 weeks, about 40 weeks to about 44 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks), the BUN level is reduced by about 0.5 mg / dL to about 5.0 mg / dL, about 0.5 mg / dL to about 4.0 mg / dL, about 0.5 mg / dL to about 3.0 mg / dL, about 0.5 mg / dL to about 2.0 mg / dL, about 0.5 mg / dL to about 1.5 mg / dL, about 1.0 mg / dL to about 5.0 mg / dL, about 1.0 mg / dL to about 4.0 mg / dL, about 1.0 mg / dL to about 3.0 mg / dL, about 1.0 mg / dL to about 2.0 mg / dL, about 1.0 mg / dL to about 1.5 mg / dL, about 1.5 mg / dL to about 5.0 mg / dL, about 1.5 mg / dL to about 4.0 mg / dL, about 1.5 mg / dL to about 3.0 mg / dL, about 1.5 mg / dL to about 2.0 mg / dL, about 2.0 mg / dL to about 5.0 mg / dL, about 2.0 mg / dL to about 4.0 mg / dL, about 2.0 mg / dL to about 3.0 mg / dL, about 3.0 mg / dL to about 5.0 mg / dL, about 3.0 mg / dL to about 4.0 mg / dL, or 4.0 mg / dL to about 5.0 mg / dL relative to the baseline.For example, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks, the BUN level can be reduced by about 50%, about 60%, or about 70%.

[0312] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in urinary neutrophil gelatinase-associated lipocalin (NGAL). In some embodiments, the subject exhibits a decrease in urinary NGAL between about 5% and about 100% (e.g., between about 10% and about 100%, between about 15% and about 100%, between about 25% and about 100%, between about 50% and about 100%, between about 75% and about 100%, between about 10% and about 75%, between about 25% and about 75%, or between about 50% and about 75%). In some embodiments, the subject exhibits a decrease in urinary NGAL of at least about 50% (e.g., at least about 55%; at least about 60%; at least about 65%; at least about 70%; at least about 75%; at least about 80%; at least about 85%; at least about 90%; or at least about 95%). In some embodiments, the subject exhibits a decrease in urinary NGAL of at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the subject exhibits a decrease in urinary NGAL of about 60%, about 70%, about 80%, or about 90%.

[0313] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease in urinary kidney injury molecule-1 (KIM-1). In some embodiments, the subject exhibits a decrease in urinary KIM-1 between about 5% and about 100% (e.g., between about 10% and about 100%, between about 15% and about 100%, between about 25% and about 100%, between about 50% and about 100%, between about 75% and about 100%, between about 10% and about 75%, between about 25% and about 75%, or between about 50% and about 75%). In some embodiments, the subject exhibits a decrease in urinary KIM-1 of at least 50% (e.g., at least 55%; at least 60%; at least 65%; at least 70%; at least 75%; at least 80%; at least 85%; at least 90%; or at least 95%). In some embodiments, the subject exhibits a decrease in urinary KIM-1 of at least 60%, at least 70%, at least 80%, or at least 90%. In some embodiments, the subject exhibits a decrease in urinary KIM-1 of about 60%, about 70%, about 80%, or about 90%.

[0314] In some embodiments, the ASBT inhibitor is administered orally. Since ASBT is mainly expressed in the ileum (where it is commonly referred to as IBAT), an ASBT inhibitor does not need to be systemically available. In fact, the systemic absorption of the vast majority of known ASBT inhibitors is low, e.g., less than 10%. However, since ASBT is also expressed in the proximal tubular cells of the kidney, systemically available ASBT inhibitors can also inhibit the reuptake of bile acids in the kidney. It is believed that this may lead to an increase in the level of bile acids in the urine and an increase in the removal of bile acids from the body through the urine. Thus, compared to non-systemically available ASBT inhibitors that act only in the ileum, systemically available ASBT inhibitors that act not only in the ileum but also in the kidney are expected to result in a greater reduction in bile acid levels. Therefore, targeting renal ASBT may be an alternative or additional means of increasing bile acid excretion in serum, liver, and kidney and reducing bile acid load in serum, liver, and kidney. Thus, in some embodiments, the ASBT inhibitor is systemically available. In some embodiments, the systemic absorption of the ASBT inhibitor is between about 10% and about 100%, e.g., between about 10% and about 75%, between about 10% and about 50%, between about 10% and about 25%, between about 25% and about 100%, between about 25% and about 75%, between about 25% and about 50%, between about 50% and about 100%, between about 50% and about 75%, or between about 75% and about 100%. In some embodiments, the systemic absorption of the ASBT inhibitor is greater than about 10%, e.g., greater than about 15%, e.g., greater than about 20%, e.g., greater than about 25%, or e.g., greater than about 30%. In some embodiments, the systemic absorption of the ASBT inhibitor is about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, or higher.

[0315] In some embodiments, the ASBT inhibitor is administered subcutaneously. It has been found that subcutaneous administration of an ASBT inhibitor can result in high bioavailability and a constant exposure lasting more than 24 hours. Thus, compared to oral administration of an ASBT inhibitor, subcutaneous administration of an ASBT inhibitor can provide a different and potentially more sustained bile acid modulating effect. This effect can be used to treat diseases in which stronger inhibition of bile acid cycling is required or when oral administration is unlikely to provide a benefit (i.e., when bile flow is blocked).

[0316] In some embodiments, oral administration of an ASBT inhibitor is combined with subcutaneous administration of an ASBT inhibitor. Such combination therapy may have additive or synergistic effects and may result in even greater excretion of bile acids. Examples of ASBT inhibitors that are not systemically available include, but are not limited to: elobixibat, obeticholic acid, maralixibat, volixibat, and linerixibat. After oral administration of these ASBT inhibitors, systemic absorption is less than 10%. Further examples of suitable ASBT inhibitors are disclosed, for example, in WO 2019 / 234077, WO 2020 / 161216, WO 2020 / 161217, WO 2021 / 110884, WO 2021 / 110885, WO 2021 / 110886, WO 2021 / 110887, and WO 2022 / 029101.

[0317] In some embodiments, a patient does not respond to treatment with an orally administered, non-systemically available ASBT inhibitor. Since subcutaneous administration of an ASBT inhibitor results in the regulation of renal ASBT, it is believed that subcutaneous administration of an ASBT inhibitor may result in stronger regulation of ASBT than oral administration of the compound.

[0318] In some embodiments, a patient cannot tolerate treatment with an orally administered, non-systemically available ASBT inhibitor, for example when the patient experiences severe side effects (such as severe diarrhea). Since subcutaneous administration of an ASBT inhibitor also results in the regulation of renal ASBT, bile acids are excreted not only in the feces but also in the urine. This is expected to result in a reduced incidence of diarrhea.

[0319] Also provided herein are methods of treating a kidney disease or disorder as defined herein in a subject, the methods comprising administering to the subject a therapeutically effective amount of an ASBT inhibitor (e.g., any of the ASBT inhibitors described herein) or a pharmaceutically acceptable salt thereof. Also provided herein is the use of an ASBT inhibitor (e.g., any of the ASBT inhibitors described herein) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a kidney disease or disorder as defined herein. In some embodiments, the kidney disease or disorder is selected from cholestatic nephropathy, chronic kidney disease, hyperbilirubinemia, renal dysfunction in obstructive jaundice, age-induced impairment of renal mitochondrial function, renal inflammation, acute kidney injury (AKI), renal ischemia / reperfusion injury (IRI), chronic kidney disease (CKD), chronic renal insufficiency, end-stage renal disease (ESRD), renal proximal tubule injury, type 1 hepatorenal syndrome, type 2 hepatorenal syndrome, and acute-on-chronic liver disease.

[0320] Combination therapy

[0321] In one aspect of the present invention, the ASBT inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with at least one other therapeutic active agent, for example, in combination with one, two, three or more other therapeutic active agents. The ASBT inhibitor or a pharmaceutically acceptable salt thereof and at least one other therapeutic active agent can be administered simultaneously, sequentially or separately. Therapeutic active agents suitable for combination with the ASBT inhibitor include, but are not limited to, known active agents useful for treating any of the diseases and disorders discussed herein.

[0322] In one embodiment, the ASBT inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with another ASBT inhibitor. Suitable ASBT inhibitors are disclosed in WO 93 / 16055, WO 94 / 18183, WO 94 / 18184, WO 96 / 05188, WO96 / 08484, WO 96 / 16051, WO 97 / 33882, WO 98 / 03818, WO 98 / 07449, WO 98 / 40375, WO 99 / 35135, WO 99 / 64409, WO 99 / 64410, WO 00 / 01687, WO 00 / 47568, WO 00 / 61568, WO 00 / 38725, WO 00 / 38726, WO 00 / 38727, WO 00 / 38728, WO 00 / 38729, WO 01 / 66533, WO 01 / 68096, WO 02 / 32428, WO 02 / 50051, WO 03 / 020710, WO 03 / 022286, WO 03 / 022825, WO 03 / 022830, WO 03 / 061663, WO 03 / 091232, WO 03 / 106482, WO 2004 / 006899, WO 2004 / 076430, WO 2007 / 009655, WO 2007 / 009656, WO 2011 / 137135, WO 2019 / 234077, WO 2020 / 161216, WO2020 / 161217, WO 2021 / 110884, WO 2021 / 110885, WO 2021 / 110886, WO 2021 / 110887, WO2022 / 029101, DE 19825804, EP 864582, EP 489423, EP 549967, EP 573848, EP 624593, EP624594, EP 624595, EP 624596, EP 0864582, EP 1173205, EP 1535913 and EP 3210977, all of which are incorporated herein by reference in their entirety.Specific examples of suitable ASBT inhibitors include 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (elobixibat) and 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (odevixibat), 1-{[4-({4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ 6 -benzothiazepine-5-yl]phenoxy}methyl)phenyl]methyl}-1,4-diazabicyclo[2.2.2]oct-1-ium chloride (maribastat), N-(3-O-benzyl-6-O-sulfo-β-D-glucopyranosyl)-N'-{3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ 6 -benzothiazepine-5-yl]phenyl}urea (volixibat) and 3-({[(3R,5R)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1λ 6 ,4-benzothiazepine-8-yl]methyl}amino)pentanedioic acid (linerixibat).

[0323] Some ASBT inhibitors can exhibit a relatively high free fraction in plasma. In some embodiments, the free fraction is from about 0% to about 100%, such as from about 0% to about 75%, from about 0% to about 50%, from about 0% to about 25%, from about 0% to about 10%, or from about 0% to about 5%. In some embodiments, the free fraction is from about 0.1% to about 100%, such as from about 0.1% to about 75%, from about 0.1% to about 50%, from about 0.1% to about 25%, from about 0.1% to about 15%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 1%, from about 1% to about 100%, from about 1% to about 75%, from about 1% to about 50%, from about 1% to about 25%, from about 1% to about 15%, from about 1% to about 10%, from about 1% to about 5%, from about 5% to about 100%, from about 5% to about 75%, from about 5% to about 50%, from about 5% to about 25%, from about 5% to about 15%, from about 5% to about 10%, from about 10% to about 100%, from about 10% to about 75%, from about 10% to about 50%, from about 10% to about 25%, from about 10% to about 15%, from about 15% to about 100%, from about 15% to about 75%, from about 15% to about 50%, from about 15% to about 25%, from about 25% to about 100%, from about 25% to about 75%, or from about 25% to about 50%. In some embodiments, the free fraction is greater than about 0.2%, such as greater than about 0.4%, such as greater than about 0.6%, such as greater than about 0.8%, such as greater than about 1.0%, such as greater than about 1.25%, such as greater than about 1.5%, such as greater than about 1.75%, such as greater than about 2.0%, such as greater than about 2.5%, such as greater than about 3%, such as greater than about 4%, such as greater than about 5%, such as greater than about 7.5%, such as greater than about 10%, or such as greater than about 20%.

[0324] Some ASBT inhibitors may be excreted in urine. In some embodiments, the fraction of the compound excreted in urine is from about 0% to about 100%, or for example from about 0% to about 75%, from about 0% to about 50%, from about 0% to about 25%, from about 0% to about 10%, or from about 0% to about 5%. In some embodiments, the fraction of the compound excreted in urine is from about 0.1% to about 100%, such as from about 0.1% to about 75%, from about 0.1% to about 50%, from about 0.1% to about 25%, from about 0.1% to about 15%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 1%, from about 1% to about 100%, from about 1% to about 75%, from about 1% to about 50%, from about 1% to about 25%, from about 1% to about 15%, from about 1% to about 10%, from about 1% to about 5%, from about 5% to about 100%, from about 5% to about 75%, from about 5% to about 50%, from about 5% to about 25%, from about 5% to about 15%, from about 5% to about 10%, from about 10% to about 100%, from about 10% to about 75%, from about 10% to about 50%, from about 10% to about 25%, from about 10% to about 15%, from about 15% to about 100%, from about 15% to about 75%, from about 15% to about 50%, from about 15% to about 25%, from about 25% to about 100%, from about 25% to about 75%, or from about 25% to about 50%. In some embodiments, the fraction of the compound excreted in urine is greater than about 0.2%, such as greater than about 0.4%, such as greater than about 0.6%, such as greater than about 0.8%, such as greater than about 1.0%, such as greater than about 2%, such as greater than about 3%, such as greater than about 5%, such as greater than about 7.5%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, such as greater than about 30%, or such as greater than about 50%.

[0325] After absorption from the intestine, some ASBT inhibitors may cycle via the enterohepatic circulation. In some embodiments, the fraction of the compound that cycles via the enterohepatic circulation is from about 0% to about 100%, such as from about 0% to about 75%, from about 0% to about 50%, from about 0% to about 25%, from about 0% to about 10%, or from about 0% to about 5%. In some embodiments, the fraction of the compound that cycles via the enterohepatic circulation is from about 0.1% to about 100%, such as from about 0.1% to about 75%, from about 0.1% to about 50%, from about 0.1% to about 25%, from about 0.1% to about 15%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 1%, from about 1% to about 100%, from about 1% to about 75%, from about 1% to about 50%, from about 1% to about 25%, from about 1% to about 15%, from about 1% to about 10%, from about 1% to about 5%, from about 5% to about 100%, from about 5% to about 75%, from about 5% to about 50%, from about 5% to about 25%, from about 5% to about 15%, from about 5% to about 10%, from about 10% to about 100%, from about 10% to about 75%, from about 10% to about 50%, from about 10% to about 25%, from about 10% to about 15%, from about 15% to about 100%, from about 15% to about 75%, from about 15% to about 50%, from about 15% to about 25%, from about 25% to about 100%, from about 25% to about 75%, or from about 25% to about 50%. In some embodiments, the fraction of the compound that cycles via the enterohepatic circulation is greater than about 0.1%, such as greater than about 0.2%, such as greater than about 0.3%, such as greater than about 0.5%, such as greater than about 1.0%, such as greater than about 1.5%, such as greater than about 2%, such as greater than about 3%, such as greater than about 5%, such as greater than about 7%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, such as greater than about 30%, or such as greater than about 50%.

[0326] Some ASBT inhibitors may cause renal excretion of bile salts. In some embodiments, the fraction of circulating bile acids excreted via the renal pathway is from about 0% to about 100%, such as from about 0% to about 75%, from about 0% to about 50%, from about 0% to about 25%, from about 0% to about 10%, or from about 0% to about 5%. In some embodiments, the fraction of circulating bile acids excreted via the renal pathway is from about 0.1% to about 100%, such as from about 0.1% to about 75%, from about 0.1% to about 50%, from about 0.1% to about 25%, from about 0.1% to about 15%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 1%, from about 1% to about 100%, from about 1% to about 75%, from about 1% to about 50%, from about 1% to about 25%, from about 1% to about 15%, from about 1% to about 10%, from about 1% to about 5%, from about 5% to about 100%, from about 5% to about 75%, from about 5% to about 50%, from about 5% to about 25%, from about 5% to about 15%, from about 5% to about 10%, from about 10% to about 100%, from about 10% to about 75%, from about 10% to about 50%, from about 10% to about 25%, from about 10% to about 15%, from about 15% to about 100%, from about 15% to about 75%, from about 15% to about 50%, from about 15% to about 25%, from about 25% to about 100%, from about 25% to about 75%, or from about 25% to about 50%. In some embodiments, the fraction of circulating bile acids excreted via the renal pathway is greater than about 1%, such as greater than about 2%, such as greater than about 5%, such as greater than about 7%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, or such as greater than about 25%.

[0327] Some ASBT inhibitors may exhibit improved or optimal permeability. Permeability can be measured in Caco2 cells and is expressed as the Papp (apparent permeability) value in cm / s. In some embodiments, the permeability is between about 0.01 x 10 -6 cm / s and about 50 x 10 -6 cm / s, such as between about 0.05 x 10 -6 cm / s and about 40 x 10 -6 cm / s, or such as between about 0.1 x 10 -6 cm / s and about 30 x 10 -6 cm / s. In some embodiments, the permeability is greater than at least about 0.1 x10 -6 cm / s, such as greater than about 0.2 x 10 -6 cm / s, such as greater than about 0.4 x 10 -6 cm / s, such as greater than about 0.7 x10 -6 cm / s, such as greater than about 1.0 x 10 -6cm / s, such as greater than about 2 x 10 -6 cm / s, such as greater than about 3 x 10 -6 cm / s, such as greater than about 5 x 10 -6 cm / s, such as greater than about 7 x 10 -6 cm / s, such as greater than about 10 x 10 -6 cm / s, such as greater than about 15 x 10 -6 cm / s.

[0328] Some ASBT inhibitors may exhibit improved or optimal bioavailability. The oral bioavailability can be between about 0% and about 100%, such as between about 1% and about 100%, between about 1% and about 90%, between about 1% and about 80%, between about 1% and about 75%, between about 1% and about 60%, between about 1% and about 50%, between about 1% and about 40%, between about 1% and about 30%, between about 1% and about 20%, between about 1% and about 10%, between about 2% and about 50%, between about 10% and about 100%, between about 10% and about 90%, between about 10% and about 80%, between about 10% and about 75%, between about 10% and about 60%, between about 10% and about 50%, between about 10% and about 40%, between about 10% and about 30%, between about 10% and about 20%, between about 20% and about 100%, between about 20% and about 90%, between about 20% and about 80%, between about 20% and about 75%, between about 20% and about 60%, between about 20% and about 50%, between about 20% and about 40%, between about 20% and about 30%, between about 30% and about 100%, between about 30% and about 90%, between about 30% and about 80%, between about 30% and about 75%, between about 30% and about 60%, between about 30% and about 50%, between about 30% and about 40%, between about 40% and about 100%, between about 40% and about 90%, between about 40% and about 80%, between about 40% and about 75%, between about 40% and about 60%, between about 40% and about 50%, between about 50% and about 100%, between about 50% and about 90%, between about 50% and about 80%, between about 50% and about 75%, between about 50% and about 60%, between about 60% and about 100%, between about 60% and about 90%, between about 60% and about 80%, between about 60% and about 75%, between about 75% and about 100%, between about 75% and about 90%, between about 75% and about 80%, between about 80% and about 100%, between about 80% and about 90%, or between about 90% and about 100%. In some embodiments, the oral bioavailability is greater than about 5%, such as greater than about 7%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, such as greater than about 30%, such as greater than about 40%, such as greater than about 50%, such as greater than about 60%, such as greater than about 70%, or such as greater than about 80%. In other embodiments, the oral bioavailability is between about 10% and about 90%, such as between about 20% and about 80%, such as between about 30% and about 70%, or such as between about 40% and about 60%.

[0329] Formulation

[0330] The ASBT inhibitor can be administered as a pharmaceutical composition, which comprises a therapeutically effective amount of the ASBT inhibitor or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Generally, the pharmaceutical composition can be prepared in a conventional manner using conventional excipients. The pharmaceutical composition can be in a form suitable for oral administration, parenteral injection (including intravenous, subcutaneous, intramuscular, and intra-arterial injection), topical administration, or rectal administration.

[0331] In some embodiments, the pharmaceutical composition is in a form suitable for oral administration (such as tablets or capsules). In addition to the ASBT inhibitor, such formulations may also contain excipients, such as fillers, binders, disintegrants, glidants, and lubricants.

[0332] Examples of suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (such as lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dried starch, hydrolyzed starch, and pregelatinized starch.

[0333] Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextran, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (such as gum arabic and tragacanth), sodium alginate, cellulose derivatives (such as hydroxypropyl methylcellulose (or hypromellose), hydroxypropyl cellulose, and ethyl cellulose), and synthetic polymers (such as acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers, and polyvinylpyrrolidone (povidone)).

[0334] Examples of suitable disintegrants include, but are not limited to, dried starch, modified starch (such as (partially) pregelatinized starch, sodium starch glycolate, and sodium carboxymethyl starch), alginic acid, cellulose derivatives (such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose (L-HPC)), and cross-linked polymers (such as carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and cross-linked PVP (crospovidone)).

[0335] Examples of suitable glidants and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, colloidal silicon dioxide, aqueous silicon dioxide, synthetic magnesium silicate, fine particle silica, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0336] The pharmaceutical composition can be conventionally coated with one or more coating layers. Also covered are enteric coating layers or coating layers for delayed or targeted release of the compound of formula (I) or its pharmaceutically acceptable salts. The coating layer can comprise one or more coating agents and can optionally comprise a plasticizer and / or a pigment (or colorant).

[0337] Examples of suitable coating agents include, but are not limited to, cellulose-based polymers (such as ethylcellulose, hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose acetate succinate, and hydroxypropylmethylcellulose phthalate), vinyl-based polymers (such as polyvinyl alcohol), and polymers based on acrylic acid and its derivatives (such as copolymers of acrylic acid and methacrylic acid, copolymers of methacrylic acid, copolymers of methyl methacrylate, copolymers of methacrylic acid aminoalkyl esters, polyacrylic acid / polymethacrylic acid copolymers).

[0338] Examples of suitable plasticizers include, but are not limited to, triethyl citrate, triacetin, tributyl citrate, diethyl phthalate, tributyl acetyl citrate, dibutyl phthalate, dibutyl sebacate, and polyethylene glycol.

[0339] Examples of suitable pigments include, but are not limited to, titanium dioxide, iron oxides (such as yellow, brown, red, or black iron oxides), and barium sulfate.

[0340] In some embodiments, the pharmaceutical composition is in a form suitable for parenteral administration (e.g., subcutaneous administration), such as a liquid (aqueous) formulation. In addition to the ASBT inhibitor, such formulations can also comprise solubilizing and stabilizing excipients, such as salts (e.g., physiological saline), buffers, surfactants, co-solvents, antioxidants, and preservatives.

[0341] Buffers can include salts (such as phosphates, citrates, acetates, gluconates, lactates, tartrates, aspartates, glutamates, and phthalates) or their corresponding acid forms, as well as histidine or Tris (tris(hydroxymethyl)aminomethane). The pH of the liquid formulation is in the range of about 4 to about 9, more preferably in the range of about 5 to about 8, and even more preferably in the range of about 6 to 7.

[0342] The surfactant can be a cationic surfactant, an anionic surfactant or a non-ionic surfactant. Examples of cationic surfactants include, but are not limited to, cetyltrimethylammonium bromide (hexadecyltrimethylammonium bromide) and cetylpyridinium chloride. Examples of anionic surfactants include, but are not limited to, sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium dodecyl sulfate (ammonium lauryl sulfate). Examples of non-ionic surfactants include, but are not limited to, glyceryl monooleate, glyceryl monostearate, polyoxyethylene castor oil (Cremophor EL), poloxamer (e.g., poloxamer 407 or 188), polysorbate 80 and sorbitan esters (Tween). In a preferred embodiment, the surfactant is a cationic surfactant.

[0343] Examples of suitable co-solvents include, but are not limited to, ethanol, propylene glycol, polyethylene glycol 400 (PEG 400), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO) and N,N-dimethylacetamide (DMA).

[0344] Examples of suitable antioxidants include, but are not limited to, butylated hydroxytoluene (BHT), ascorbyl palmitate, propyl gallate and ascorbic acid and combinations thereof.

[0345] Examples of suitable preservatives include, but are not limited to, phenol, benzyl alcohol, methyl paraben, ethyl paraben, propyl paraben, ethylenediaminetetraacetic acid (EDTA), potassium sorbate and sodium benzoate, and combinations thereof.

[0346] In some embodiments, the concentration of the ASBT inhibitor in the liquid formulation is from about 0.001 to about 30 mg / mL. In some embodiments, the concentration of the ASBT inhibitor in the liquid formulation is from about 0.01 to about 10 mg / mL, such as from about 0.01 to about 5 mg / mL, from about 0.01 to about 2 mg / mL, from about 0.01 to about 1.5 mg / mL, from about 0.01 to about 1.0 mg / mL, from about 1 to about 10 mg / mL, from about 1 to about 5 mg / mL, from about 1 to about 2 mg / mL, from about 1 to about 1.5 mg / mL, from about 2 to about 10 mg / mL, from about 2 to about 5 mg / mL, from about 5 to about 10 mg / mL; or such as from about 10 to about 30 mg / mL, such as from about 10 to about 20 mg / mL, or such as from about 20 to about 30 mg / mL. In some embodiments, the concentration of the ASBT inhibitor in the liquid formulation is about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about 1.2 mg / mL, about 1.4 mg / mL, about 1.6 mg / mL, about 1.8 mg / mL or about 2.0 mg / mL.

[0347] In some embodiments, the pharmaceutical composition optionally comprises one or more additional therapeutic agents as described herein.

[0348] Dosage and frequency of administration

[0349] The dosage required for therapeutic or prophylactic treatment will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors that a treating physician typically considers in determining the appropriate regimen and dosage level for a particular patient.

[0350] The amount of the ASBT inhibitor to be administered will vary depending on the patient being treated and can range from about 1 µg / kg of body weight per day to about 50 mg / kg of body weight. In some embodiments, an ASBT inhibitor or a pharmaceutically acceptable salt thereof is administered to a patient at about 1 μg / kg / day to about 50 mg / kg / day, such as about 1 µg / kg / day to about 25 mg / kg / day, about 1 µg / kg / day to about 10 mg / kg / day, about 1 µg / kg / day to about 5 mg / kg / day, about 1 µg / kg / day to about 1 mg / kg / day, about 1 µg / kg / day to about 800 µg / kg / day, about 1 µg / kg / day to about 400 µg / kg / day, about 1 µg / kg / day to about 200 µg / kg / day, about 1 µg / kg / day to about 160 µg / kg / day, about 1 µg / kg / day to about 140 µg / kg / day, about 1 µg / kg / day to about 120 µg / kg / day, about 1 µg / kg / day to about 100 µg / kg / day, about 1 µg / kg / day to about 75 µg / kg / day, about 1 µg / kg / day to about 50 µg / kg / day, about 1 µg / kg / day to about 25 µg / kg / day, about 1 µg / kg / day to about 10 µg / kg / day, about 50 µg / kg / day to about 50 mg / kg / day, about 50 µg / kg / day to about 25 mg / kg / day, about 50 µg / kg / day to about 10 mg / kg / day, about 50 µg / kg / day to about 5 mg / kg / day, about 50 µg / kg / day to about 1 mg / kg / day, about 50 µg / kg / day to about 800 µg / kg / day, about 50 µg / kg / day to about 400 µg / kg / day, about 50 µg / kg / day to about 200 µg / kg / day, about 50 µg / kg / day to about 160 µg / kg / day, about 50 µg / kg / day to about 140 µg / kg / day, about 50 µg / kg / day to about 120 µg / kg / day, about 50 µg / kg / day to about 100 µg / kg / day, about 50 µg / kg / day to about 75 µg / kg / day, about 200 µg / kg / day to about 50 mg / kg / day, about 200 µg / kg / day to about 25 mg / kg / day, about 200 µg / kg / day to about 10 mg / kg / day, about 200 µg / kg / day to about 5 mg / kg / day, about 200 µg / kg / day to about 1 mg / kg / day, about 200 µg / kg / day to about 800 µg / kg / day, about 200 µg / kg / day to about 400 µg / kg / day, about 400 µg / kg / day to about 50 mg / kg / day, about 400 µg / kg / day to about 25An ASBT inhibitor or a pharmaceutically acceptable salt thereof at a dose of mg / kg / day, about 400 µg / kg / day to about 10 mg / kg / day, about 400 µg / kg / day to about 5 mg / kg / day, about 400 µg / kg / day to about 1 mg / kg / day, about 400 µg / kg / day to about 800 µg / kg / day, about 800 µg / kg / day to about 50 mg / kg / day, about 800 µg / kg / day to about 25 mg / kg / day, about 800 µg / kg / day to about 10 mg / kg / day, about 800 µg / kg / day to about 5 mg / kg / day, about 800 µg / kg / day to about 1 mg / kg / day, about 5 mg / kg / day to about 50 mg / kg / day, about 5 mg / kg / day to about 25 mg / kg / day or about 5 mg / kg / day to about 10 mg / kg / day.

[0351] Unit dosage forms (e.g., tablets or capsules) generally contain from about 0.1 to about 250 mg of the active ingredient, such as from about 0.1 to about 150 mg, from about 0.1 to about 100 mg, from about 0.1 to about 75 mg, from about 0.1 to about 50 mg, from about 0.1 to about 20 mg, such as about 0.2 mg, about 0.4 mg, about 0.6 mg, about 1.2 mg, about 2.5 mg, about 5 mg, about 10 mg or about 15 mg. In some embodiments, the unit dosage form (e.g., tablet or capsule) contains from about 10 mg to about 250 mg, 10 mg to about 200 mg, 10 mg to about 150 mg, 10 mg to about 100 mg, 10 mg to about 100 mg, 10 mg to about 75 mg, 10 mg to about 50 mg, from about 50 mg to about 250 mg, 50 mg to about 200 mg, 50 mg to about 150 mg, 50 mg to about 100 mg, 50 mg to about 100 mg, 50 mg to about 75 mg, from about 75 mg to about 250 mg, 75 mg to about 200 mg, 75 mg to about 150 mg, 75 mg to about 100 mg, 75 mg to about 100 mg, from about 100 mg to about 250 mg, 100 mg to about 200 mg, 100 mg to about 150 mg, from about 150 mg to about 250 mg, 150 mg to about 200 mg or from about 200 mg to about 250 mg. The daily dose can be administered as a single dose, or divided into one, two, three or more unit doses. The oral daily dose of the bile acid modulator is preferably within from about 0.1 to about 250 mg, more preferably within from about 0.1 to about 100 mg, such as within from about 0.1 to about 20 mg, within from about 0.1 to about 15 mg, within from about 0.1 to about 10 mg, within from about 0.1 to about 9 mg, within from about 0.1 to about 8 mg, within from about 1 to about 7 mg, within from about 1 to about 6 mg, within from about 0.1 to about 5 mg, within from about 0.1 to about 4 mg, within from about 0.1 to about 3 mg, within from about 0.1 to about 2 mg, within from about 0.1 to about 1 mg, within from about 1 to about 10 mg, within from about 1 to about 9 mg, within from about 1 to about 8 mg, within from about 1 to about 7 mg, within from about 1 to about 6 mg, within from about 1 to about 5 mg, within from about 1 to about 4 mg, within from about 1 to about 3 mg, within from about 1 to about 2 mg, within from about 2 to about 5 mg, within from about 2 to about 8 mg, within from about 2 to about 10 mg, within from about 5 to about 10 mg, within from about 5 to about 8 mg or within from about 8 to about 10 mg.

[0352] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more symptoms thereof as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., based on a symptom history and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

[0353] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human.

[0354] As used herein, the term "baseline" refers to information obtained prior to the first administration of a drug or intervention of interest (e.g., at the start of a study), or an initial known value used for comparison with subsequent data. Baseline values are taken at time "zero" (i.e., before a subject in a study receives a drug or intervention of interest or a placebo).

[0355] As used herein, the term "normalized" refers to a value specific to age that is within the range corresponding to healthy individuals (i.e., normal values or normalized values).

[0356] As used herein, the term "about" refers to a value or parameter herein that includes (and describes) embodiments directed to the value or parameter itself. For example, a description that refers to "about 20" includes a description of "20". Numerical ranges include the numbers defining the range. Generally, the term "about" refers to an indicated value of a variable, and all variable values within the experimental error of the indicated value (e.g., within 95% confidence interval of the mean) or within 10% of the indicated value (whichever is greater). Examples

[0357] ASBT inhibitor compounds 1 to 5 were used in the experiments described herein. The potency (hIBATIC 50 ), permeability, and bioavailability of these compounds are shown in Table 1 below. The values were determined using assays such as those described in WO 2020 / 161217.

[0358] Table 1.

[0359]

[0360] Example 1

[0361] Biliary nephropathy mouse model - bile duct ligation (BDL) in mice

[0362] Time-resolved events in the liver and kidneys after extrahepatic common bile duct ligation were evaluated.

[0363] Male mice (C57BL / 6n) were used. After completion of the quarantine and acclimation periods, animals were randomly assigned to experimental groups (n = 5 mice per group and time point) based on body weight. On day 0, animals underwent bile duct ligation or sham surgery. Animals were euthanized after 1 or 3 days or after 1, 3, 6, 9, or 12 weeks, and samples (bile, blood, urine, liver, and kidney tissues) were collected and analyzed.

[0364] BDL led to excessive accumulation of bile in the gallbladder and caused an increase in serum ALT and AST, which peaked on day 1 and then decreased as the liver adapted to cholestasis but remained higher than control values ( Figure 1A and 1B ). Alkaline phosphatase (ALP) enzyme activity showed a time-dependent increase after BDL ( Figure 1C ).

[0365] Analysis of the expression of bile acid transporters showed that ASBT was strongly downregulated after BDL. Figure 2A -D shows the compensatory changes in bile acid transporter expression during 12 weeks after BDL or sham surgery. Figure 2A : Sinusoidal uptake transporter NTCP; Figure 2B : Sinusoidal uptake transporter Cyp7a1; Figure 2C : Apical transporter Bsep; Figure 2D : Sinusoidal efflux transporter MRP4. Figure 3A -E shows the expression of apical uptake transporters ASBT ( Figure 3A ) and OATP1a1 ( Figure 3B ), apical efflux transporter MRP4 ( Figure 3C ), and basolateral efflux transporters MRP3 ( Figure 3D ) and OSTα ( Figure 3E ) during 12 weeks after BDL or sham surgery.

[0366] Similar studies were conducted using female mice.

[0367] Example 2

[0368] Effect of ASBT inhibition in BDL mice

[0369] The short-term effect of oral administration of compound 1 on the urinary excretion of bile acids in BDL mice was evaluated.

[0370] Female mice (C57BL / 6n) were used. After completion of the quarantine and acclimation periods, the animals were randomly divided into experimental groups (n = 4 - 7 mice per group) based on body weight. On day 0, the animals underwent bile duct ligation. Starting on day 7, the animals were treated with vehicle or different doses of compound 1 for 5 days, as shown in Table 2. Compound 1 was administered orally by gavage, twice daily. Spontaneous urine samples were collected by bladder catheterization before BDL and on days 7, 8, 9, 10, 11, and 12 after BDL, and the concentration of bile acids in the urine was determined.

[0371] Table 2.

[0372]

[0373] The dose - dependent study showed that during the 5 - day analysis period, urinary bile acids increased strongly due to ASBT inhibition. After treatment with compound 1, the urinary excretion of bile acids increased sharply, with bile acid concentrations in all treatment groups at least about 20 - fold higher. The results are shown in Figure 4 (total concentration of all bile acids) and Figure 5A -C (concentrations of the individual bile acids tauro - α / β - muricholate, taurocholate, and taurocholic acid sulfate, respectively).

[0374] Example 3

[0375] Effect of ASBT inhibition on biliary nephropathy in bile duct - ligated mice

[0376] The long - term effect of compound 1 on kidney injury in BDL mice was investigated by histology, clinical chemistry, and in vivo imaging.

[0377] Female mice (C57BL / 6n) were used. After completion of the quarantine and acclimation periods, the animals were randomly divided into experimental groups (n = 15 mice per group) based on body weight. On day 0, the animals underwent bile duct ligation or sham surgery. The animals were treated with vehicle or with compound 1 at a dose of 60 mg / kg, as shown in Table 3. Compound 1 was administered orally by gavage, twice daily. Spontaneous urine samples were collected by bladder catheterization before BDL and on days 1 and 1, 2, 3, 4, 5, and 6 weeks after BDL. At the end of the experiment (week 6), blood, urine, bile, and tissue samples were collected.

[0378] Table 3.

[0379]

[0380] Severe fibrosis and cystic dilation of the renal tubules were observed in the BDL vehicle control, and Compound 1 almost antagonized it to the level of control animals without BDL. The urinary kidney injury markers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) were strongly reduced by Compound 1 (see Figure 13 and Figure 14 respectively). In addition, serum BA was reduced by approximately 90% (total bile acids see Figure 6 , individual bile acids see Figures 7 - 10 ), and urinary BA increased significantly. In vivo imaging with Evans blue showed severe vascular leakage in the kidneys after BDL, which was completely reversed by Compound 1.

[0381] The levels of liver enzymes (ALT, AST, and ALP), total bilirubin, and blood urea nitrogen (BUN) after 6 weeks of treatment are shown in Figure 15. The expression of different bile acid transporters after 6 weeks of treatment is shown in Figures 16 and 17.

[0382] In the BDL-vehicle group, approximately 50% of the mice died during the 6-week period, while no deaths occurred in the group of BDL mice treated with Compound 1 (see Figure 12 ). In addition, the weight loss caused by BDL was strongly improved by ASBT inhibition (see Figure 11 ). A similarly designed study using male mice (6 per group) confirmed the therapeutic efficacy of Compound 1 observed in the female cohort.

[0383] Example 4

[0384] Study of the treatment time window

[0385] The effect of the time period before starting treatment with Compound 1 on renal injury in BDL mice was evaluated.

[0386] Male mice (C57BL / 6n) were administered. After completion of the quarantine and acclimation periods, the animals were randomly divided into experimental groups (n = 7 mice per group) based on body weight. On day 0, the animals underwent bile duct ligation or sham surgery. Starting on day 3, 21, 42, or 63, the animals were treated with vehicle or with Compound 1 at a dose of 60 mg / kg for 28 days, as shown in Table 4 below. Compound 1 was administered p.o. twice a day. The animals were weighed daily. Blood, urine, bile, and tissue samples were collected at the end of the experiment.

[0387] Table 4.

[0388]

[0389] Graphs of the survival rate (%) of the four groups are shown in Figure 18. Graphs of the weight change (%) of the four groups after sham surgery or BDL are shown in Figure 19.

[0390] When the administration started on day 3, 4-week treatment with Compound 1 completely prevented kidney injury and reversed weight loss. When the administration started on day 21, Compound 1 almost completely reversed kidney injury and reversed weight loss. When the administration started on day 42, Compound 1 partially reversed kidney injury and reversed weight loss. When the administration started on day 63, Compound 1 had a minimal effect.

[0391] Example 5

[0392] Comparison of different ASBT inhibitors

[0393] Male mice (C57BL / 6n) were used. After completion of the quarantine and acclimation periods, the animals were randomly divided into experimental groups based on body weight (n = 12 mice per bile duct ligation group and n = 5 mice for sham operation control). On day 0, the animals underwent bile duct ligation or sham operation. Starting on day 3, the animals were treated with vehicle or an ASBT inhibitor for 19 days as shown in Table 5 below. The ASBT inhibitor was administered p.o. once daily. The animals were weighed daily. On day 21, blood samples were collected 2 hours and 6 hours after the last dose. On day 24, the animals were sacrificed and samples (urine and blood; liver, kidney, heart, and spleen tissues) were collected and analyzed.

[0394] Table 5.

[0395]

[0396] After 19 days of treatment, it was observed that Compounds 1 and 2 decreased serum bile acids and increased urinary bile acids. Figure 20A and 20B show the concentrations of total bile acids in blood and urine on day 21 (i.e., the 19th day of treatment), respectively. After 18 days of treatment, Compounds 1 and 2 also decreased urinary NGAL; see Figure 21 .

[0397] Example 6

[0398] Comparison of different ASBT inhibitors

[0399] Male mice (C57BL / 6n) were used. After completion of the quarantine and acclimation periods, the animals were randomly divided into experimental groups (n = 10 mice per bile duct ligation group) based on body weight. On day 1, the animals underwent bile duct ligation. Starting from day 4, the animals were treated with either vehicle or an ASBT inhibitor for 5 days as shown in Table 6 below. The ASBT inhibitor was administered p.o. once daily. The animals were weighed daily. On day 6, the animals were moved to individual cages for cumulative overnight fecal collection (days 6 to 7). On day 8, blood samples were collected 2 and 6 hours after the last dose. The animals were then sacrificed and samples (urine and blood; liver, kidney, and ileum tissues) were collected and analyzed.

[0400] Table 6.

[0401]

[0402] After 5 days of treatment, all compounds were observed to reduce serum bile acids and increase urinary bile acids. The concentrations of total bile acids in blood and urine on day 8 (i.e., day 5 of treatment) are shown in Figure 22A and 22B respectively. After 5 days of treatment, compound X and compound 5 significantly reduced urinary NGAL; see Figure 23 .

[0403] The concentrations of compound X and compound 5 in serum (2 and 6 hours after dosing) and urine (up to 6 hours after dosing) on day 8 are shown in Figures 24 and 25, respectively.

Claims

1. An ASBT inhibitor or a pharmaceutically acceptable salt thereof, which is used for treating kidney diseases or disorders.

2. The ASBT inhibitor used according to claim 1, wherein the kidney disease or disorder is a bile acid-dependent kidney disease or disorder.

3. The ASBT inhibitor used according to claim 1, wherein the kidney disease or disorder is selected from cholestatic nephropathy, chronic kidney disease, hyperbilirubinemia, obstructive jaundice-induced renal dysfunction, aging-induced impaired kidney mitochondrial function, kidney inflammation, acute kidney injury (AKI), kidney ischemia / reperfusion injury (IRI), chronic kidney disease (CKD), chronic renal insufficiency, end-stage renal disease (ESRD), kidney proximal tubule injury, type 1 hepatorenal syndrome, type 2 hepatorenal syndrome, and acute-on-chronic liver disease.

4. The ASBT inhibitor used according to claim 1, wherein the kidney disease or disorder is cholestatic nephropathy.

5. The ASBT inhibitor used according to claim 1, wherein the ASBT inhibitor is (Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoracrylic acid, or a pharmaceutically acceptable salt thereof.

6. The ASBT inhibitor used according to claim 1, wherein the ASBT inhibitor is selected from elobixibat, obeticholic acid, maralixibat, volixibat, and linerixibat, or a pharmaceutically acceptable salt thereof.

7. The ASBT inhibitor used according to claim 1, wherein the ASBT inhibitor is administered orally.

8. The ASBT inhibitor used according to claim 1, wherein the systemic absorption of the ASBT inhibitor is greater than 10%.

9. The ASBT inhibitor used according to claim 1, wherein the ASBT inhibitor is administered subcutaneously.

10. The ASBT inhibitor used according to claim 8, wherein the patient also receives treatment with an orally administered, non-systemically available ASBT inhibitor.

11. The ASBT inhibitor used according to claim 1, wherein the subject exhibits a decrease in serum bile acid concentration after administration of the ASBT inhibitor.

12. The ASBT inhibitor used according to claim 11, wherein the serum bile acid concentration is reduced by at least 60%, at least 70%, at least 80%, or at least 90% relative to the baseline.

13. The ASBT inhibitor used according to claim 11, wherein the serum bile acid concentration normalizes after administration of the ASBT inhibitor.

14. The ASBT inhibitor used according to claim 1, wherein the subject exhibits an increase in urinary bile acids after administration of the ASBT inhibitor.

15. The ASBT inhibitor used according to claim 14, wherein the urinary bile acids increase by at least 60%, at least 70%, at least 80%, or at least 90% relative to the baseline.

16. The ASBT inhibitor used according to claim 1, wherein the subject shows an improvement in liver parameters after administration of the ASBT inhibitor.

17. The ASBT inhibitor used according to claim 16, wherein the liver parameters are selected from serum total bilirubin level, serum alkaline phosphatase (ALP) level, serum alanine aminotransferase (ALT) level, and serum aspartate aminotransferase (AST) level.

18. The ASBT inhibitor used according to claim 16, wherein the improvement in the liver parameters occurs at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, or at least 48 weeks after administration of the ASBT inhibitor.

19. The ASBT inhibitor used according to claim 1, wherein the subject shows a decrease in urinary neutrophil gelatinase-associated lipocalin (NGAL) after administration of the ASBT inhibitor.

20. The ASBT inhibitor used according to claim 19, wherein the decrease in urinary NGAL is at least 60%, at least 70%, at least 80%, or at least 90%.

21. The ASBT inhibitor used according to claim 1, wherein the subject shows a decrease in urinary kidney injury molecule-1 (KIM-1) after administration of the ASBT inhibitor.

22. The ASBT inhibitor used according to claim 21, wherein the decrease in urinary KIM-1 is at least 60%, at least 70%, at least 80%, or at least 90%.

23. The ASBT inhibitor used according to claim 1, wherein the subject shows a decrease in serum blood urea nitrogen (BUN) after administration of the ASBT inhibitor.

24. The ASBT inhibitor used according to claim 1, wherein the ASBT inhibitor is administered once daily.

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